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Levin, Edward Daniel

Overview:

Dr. Levin is Chief of the Neurobehavioral Research Lab in the Psychiatry Department of Duke University Medical Center. His primary academic appointment is as Professor in the Department of Psychiatry and Behavioral Sciences. He also has secondary appointments in the Department Pharmacology and Cancer Biology, the Department of Psychological and Brain Sciences and the Nicholas School of the Environment at Duke. His primary research effort is to understand basic neural interactions underlying cognitive function and addiction and to apply this knowledge to better understand cognitive dysfunction and addiction disorders and to develop novel therapeutic treatments.

The three main research components of his laboratory are focused on the themes of the basic neurobiology of cognition and addiction, neurobehavioral toxicology and the development of novel therapeutic treatments for cognitive dysfunction and substance abuse. Currently, our principal research focus concerns nicotine. We have documented the basic effects of nicotine on learningm memory and attention as well as nicotine self-administration. We are continuing with more mechanistic studies in rat models using selective lesions, local infusions and neurotransmitter interaction studies. We have found that nicotine improves memory performance not only in normal rats, but also in rats with lesions of hippocampal and basal forebrain connections. We are concentrating on alpha7 and alpha4beta2 nicotinic receptor subtypes in the hippocampus, amygdala , thalamus and frontal cortex and how they interact with dopamine D1 and D2 and glutamate NMDA systems with regard to memory and addiction. I am also conducting studies on human cognitive behavior. We have current studies to assess nicotine effects on attention, memory and mental processing speed in schizophrenics, Alzheimer's Disease patients and people with Attention Deficit Hyperactivity Disorder. In the area of neurobehavioral toxicology, I have continuing projects to characterize the adverse effects of prenatal and adolescent nicotine exposure. Our primary project in neurobehavioral toxicology focuses on the cognitive deficits caused by the marine toxins including domoic acid, ciguatera toxin and pfiesteria. We have documented a persistent neurobehavioral effects caused by Pfiesteria and domoic acid exposure. We are determining the neurobehavioral nature and mechanisms of this deficit. The basic and applied aims of our research complement each other nicely. The findings concerning neural mechanisms underlying cognitive function help direct the behavioral toxicology and therapeutic development studies, while the applied studies provide important functional information concerning the importance of the basic mechanisms under investigation.

Positions:

Professor in Psychiatry and Behavioral Sciences

Psychiatry & Behavioral Sciences, Addictions
School of Medicine

Professor in the Environmental Sciences and Policy Division

Environmental Sciences and Policy
Nicholas School of the Environment

Associate Professor of Pharmacology & Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Professor of Psychology and Neuroscience

Psychology and Neuroscience
Trinity College of Arts & Sciences

Affiliate of the Duke Initiative for Science & Society

Duke Science & Society
Institutes and Provost's Academic Units

Faculty Network Member of the Duke Institute for Brain Sciences

Duke Institute for Brain Sciences
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Director, Integrated Toxicology Program

School of Medicine
School of Medicine

Education:

Ph.D. 1984

Ph.D. — University of Wisconsin at Madison

News:

Grants:

Pharmacological Sciences Training Program

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Participating Faculty Member
Start Date
July 01, 1975
End Date
June 30, 2020

Duke University Program in Environmental Health

Administered By
Environmental Sciences and Policy
AwardedBy
National Institute of Environmental Health Sciences
Role
Mentor
Start Date
July 01, 2013
End Date
June 30, 2018

Acute and chronic nicotine modulation of reinforcement learning

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
April 01, 2013
End Date
March 31, 2018

Establishing an AOP for the Role of the Vitamin D Receptor in Developmental Neurotoxicity

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
North Carolina State University
Role
Principal Investigator
Start Date
August 01, 2013
End Date
January 31, 2018

Pilot Project: Effects of Cannabis on the Epigenome of Humans and Rats

Administered By
Obstetrics and Gynecology, Gynecologic Oncology
AwardedBy
John Templeton Foundation
Role
Co-Project Leader
Start Date
February 01, 2016
End Date
July 31, 2017

Screening Potential Persisting Neurobehavioral Effects-Zebrafish Exposed to Flame Retardants

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
National Institute of Environmental Health Sciences
Role
Principal Investigator
Start Date
September 13, 2015
End Date
May 01, 2017

Complementary Neurotoxicological Insights from Fish, Flies, Bees and Worms Symposium

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2015
End Date
June 30, 2016

Nicotinic Receptor Desensitization to Reduce Drug Self-Administration: Project 2

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
Georgetown University
Role
Principal Investigator
Start Date
March 15, 2010
End Date
February 28, 2015

Atrazine Effects in the Brain: Pilot Study

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
Environmental Protection Agency
Role
Principal Investigator
Start Date
September 29, 2011
End Date
September 28, 2012

Role of HPA Axis in Adolescent Vulnerability to Drug Addiction

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
September 30, 2006
End Date
June 30, 2011

Neurobehavioral Teratology Society: Zebrafish Symposium

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 01, 2010
End Date
May 31, 2011

Adolescence: A Sensitive Period for Nicotine Addiction

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2004
End Date
March 31, 2010

MARCKS Peptides and Memory

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 04, 2009
End Date
February 03, 2010

Neuroimaging Attentional Impairment During Abstinence

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
July 01, 2004
End Date
June 30, 2009

Nicotinic-Antipsychotic Drug Interactions and Cognition

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
December 12, 2001
End Date
November 30, 2006

Marine Toxin Impacts on Neurobehavioral Function

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2003
End Date
March 31, 2004

Non-Monotonic Dose-Toxicity Functions, Multiple Mechanisms of Effect: Impacts on Health & Public Policy

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
Environmental Protection Agency
Role
Principal Investigator
Start Date
December 17, 2002
End Date
February 28, 2004

Collaberative Research Training In Enviromental Toxicology

Administered By
Psychiatry & Behavioral Sciences, Translational Neuroscience
AwardedBy
Environmental Protection Agency
Role
Principal Investigator
Start Date
January 01, 1998
End Date
April 28, 2003

Behavioral Genetics and Toxic Response

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 15, 2002
End Date
February 14, 2003

Chronic Nicotine-Infusion Induced Memory Improvement

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 20, 1998
End Date
June 30, 2002

Smoking, Schhizophrenia, and Atypical Antipsychotics

Administered By
Psychiatry & Behavioral Sciences, Translational Neuroscience
AwardedBy
National Institutes of Health
Role
Administrative Assistant
Start Date
July 01, 1997
End Date
November 30, 1999

Neurotoxic Effects of Adult and Developmental Exposure to Pfiesteria Toxin

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
Environmental Protection Agency
Role
Principal Investigator
Start Date
September 30, 1998
End Date
July 30, 1999

Attention as a Target of Intoxication

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 15, 1999
End Date
June 30, 1999

Integrated Toxicology

Administered By
Psychiatry & Behavioral Sciences, Translational Neuroscience
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1995
End Date
June 30, 1999

Drive To Smoke And Dopamine Blockade

Administered By
Psychiatry & Behavioral Sciences, Translational Neuroscience
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
July 01, 1994
End Date
November 30, 1997

The Effect Of Pfiesteriaon Learning And Memory In Rats

Administered By
Psychiatry & Behavioral Sciences, Translational Neuroscience
AwardedBy
Environmental Protection Agency
Role
Principal Investigator
Start Date
May 15, 1997
End Date
November 15, 1997

Neurobehavioral Effects Of Dinoflagellate Toxins In Rat

Administered By
Psychiatry & Behavioral Sciences, Translational Neuroscience
AwardedBy
NC Sea Grant
Role
Principal Investigator
Start Date
March 01, 1996
End Date
September 30, 1997

Cholinergic-Dopaminergic Interactions And The Foundations

Administered By
Psychiatry & Behavioral Sciences, Translational Neuroscience
AwardedBy
National Science Foundation
Role
Principal Investigator
Start Date
September 01, 1992
End Date
July 14, 1997

Scaling The Reinforcing Value Of Cigarette Smoke

Administered By
Psychiatry & Behavioral Sciences, Translational Neuroscience
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1993
End Date
August 31, 1994

Cholinergic-Dopaminergic Interactions & The Foundations Of

Administered By
Psychiatry & Behavioral Sciences, Translational Neuroscience
AwardedBy
National Science Foundation
Role
Principal Investigator
Start Date
May 27, 1993
End Date
August 31, 1994
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Publications:

Developmental neurotoxicity of succeeding generations of insecticides.

Insecticides are by design toxic. They must be toxic to effectively kill target species of insects. Unfortunately, they also have off-target toxic effects that can harm other species, including humans. Developmental neurotoxicity is one of the most prominent off-target toxic risks of insecticides. Over the past seven decades several classes of insecticides have been developed, each with their own mechanisms of effect and toxic side effects. This review covers the developmental neurotoxicity of the succeeding generations of insecticides including organochlorines, organophosphates, pyrethroids, carbamates and neonicotinoids. The goal of new insecticide development is to more effectively kill target species with fewer toxic side effects on non-target species. From the experience with the developmental neurotoxicity caused by the generations of insecticides developed in the past advice is offered how to proceed with future insecticide development to decrease neurotoxic risk.

Authors
Abreu-Villaça, Y; Levin, ED
MLA Citation
Abreu-Villaça, Y, and Levin, ED. "Developmental neurotoxicity of succeeding generations of insecticides." Environment international 99 (February 2017): 55-77.
PMID
27908457
Source
epmc
Published In
Environment International
Volume
99
Publish Date
2017
Start Page
55
End Page
77
DOI
10.1016/j.envint.2016.11.019

The ventral hippocampal muscarinic cholinergic system plays a key role in sexual dimorphisms of spatial working memory in rats.

Sex differences in cognitive processing and function have been documented in human and animal studies. Females have been found to perform better than males on non-spatial memory tasks, while males tend to outperform females on spatial memory tasks. The neural mechanisms underlying these sexual dimorphisms are unclear. However, it is known that the cholinergic system is critically involved in memory processes, and there are notable differences between males and females in cholinergic system function and receptor expression. In particular, there are sex differences in the processing of information in the frontal cortex and hippocampus. In this study, we examined the roles of muscarinic and nicotinic acetylcholine receptors in the medial frontal cortex (MfC) and ventral hippocampus (VH) on spatial working memory in male and female rats. Local infusions of scopolamine (SCOP) and mecamylamine (MEC) (10, 20, 50 μg/side) were used to antagonize these receptors in each respective brain region during performance in the 16-arm radial arm maze. Infusions of SCOP into the VH caused a significant increase in memory errors in female rats, but had no significant effect on males, while infusions of MEC into the VH had no effect on either sex. Infusions of both SCOP (50 μg/side) and MEC (20 μg/side) into the MfC caused working memory impairments in both sexes. These results show that muscarinic acetylcholine receptors in the VH are differentially vulnerable to spatial memory impairments in females. Ventral hippocampal muscarinic acetylcholine receptors may play a key role in male-female differences in spatial memory.

Authors
Hall, BJ; Abreu-Villaça, Y; Cauley, M; Junaid, S; White, H; Kiany, A; Levin, ED
MLA Citation
Hall, BJ, Abreu-Villaça, Y, Cauley, M, Junaid, S, White, H, Kiany, A, and Levin, ED. "The ventral hippocampal muscarinic cholinergic system plays a key role in sexual dimorphisms of spatial working memory in rats." Neuropharmacology 117 (January 25, 2017): 106-113.
PMID
28131771
Source
epmc
Published In
Neuropharmacology
Volume
117
Publish Date
2017
Start Page
106
End Page
113
DOI
10.1016/j.neuropharm.2017.01.019

Persisting neurobehavioral effects of developmental copper exposure in wildtype and metallothionein 1 and 2 knockout mice.

Metallothioneins (MT) are small proteins, which are crucial for the distribution of heavy and transition metals. Previously, we found in mice that knockout of MT 1 and 2 genes (MTKO) impaired spatial learning and potentiated the learning impairment caused by developmental mercury exposure. The current study examined the neurocognitive and neurochemical effects of MTKO with the developmental copper (Cu) supplementation.Wildtype (WT) and MTKO mice were given supplemental Cu (0, 10 or 50 mg/l) in their drinking water during gestation and until weaning. When the mice were young adults they were trained on the win-shift 8-arm radial maze test of spatial learning and memory. After cognitive testing, their brains were analyzed for norepinepherine, dopamine and serotonin levels.In the spatial learning test, wildtype mice showed the normal sex difference with males performing more accurately than the females. This effect was eliminated by MTKO and restored by moderate Cu supplementation during development. In neurochemical studies, MTKO caused a significant overall increase in serotonin in all of the regions studied: the frontal cortex, posterior cortex, hippocampus, striatum, midbrain, and brainstem. MTKO also caused a significant increase in norepinepherine in the brainstem and hippocampus. In wildtype mice, Cu supplementation during development caused a significant decline in dopamine and norepinepherine in the midbrain and dopamine in the frontal cortex. These effects were blocked by MTKO.The normal sex difference in spatial working memory accuracy, which was eliminated by MTKO, was restored by moderate copper supplementation. MTKO increased serotonin across all brain areas studied and increased norepinepherine only in the hippocampus and brainstem. MTKO blocked copper-induced decreases in dopamine and norepinepherine in the midbrain and dopamine in the frontal cortex.

Authors
Petro, A; Sexton, HG; Miranda, C; Rastogi, A; Freedman, JH; Levin, ED
MLA Citation
Petro, A, Sexton, HG, Miranda, C, Rastogi, A, Freedman, JH, and Levin, ED. "Persisting neurobehavioral effects of developmental copper exposure in wildtype and metallothionein 1 and 2 knockout mice." BMC pharmacology & toxicology 17.1 (November 2, 2016): 55-.
PMID
27802831
Source
epmc
Published In
BMC pharmacology & toxicology
Volume
17
Issue
1
Publish Date
2016
Start Page
55

Diverse neurotoxicants target the differentiation of embryonic neural stem cells into neuronal and glial phenotypes.

The large number of compounds that needs to be tested for developmental neurotoxicity drives the need to establish in vitro models to evaluate specific neurotoxic endpoints. We used neural stem cells derived from rat neuroepithelium on embryonic day 14 to evaluate the impact of diverse toxicants on their ability to differentiate into glia and neurons: a glucocorticoid (dexamethasone), organophosphate insecticides (chlorpyrifos, diazinon, parathion), insecticides targeting the GABAA receptor (dieldrin, fipronil), heavy metals (Ni2+, Ag+), nicotine and tobacco smoke extract. We found three broad groupings of effects. One diverse set of compounds, dexamethasone, the organophosphate pesticides, Ni2+ and nicotine, suppressed expression of the glial phenotype while having little or no effect on the neuronal phenotype. The second pattern was restricted to the pesticides acting on GABAA receptors. These compounds promoted the glial phenotype and suppressed the neuronal phenotype. Notably, the actions of compounds eliciting either of these differentiation patterns were clearly unrelated to deficits in cell numbers: dexamethasone, dieldrin and fipronil all reduced cell numbers, whereas organophosphates and Ni2+ had no effect. The third pattern, shared by Ag+ and tobacco smoke extract, clearly delineated cytotoxicity, characterized by major cell loss with suppression of differentiation into both glial and neuronal phenotypes; but here again, there was some selectivity in that glia were suppressed more than neurons. Our results, from this survey with diverse compounds, point to convergence of neurotoxicant effects on a specific "decision node" that controls the emergence of neurons and glia from neural stem cells.

Authors
Slotkin, TA; Skavicus, S; Card, J; Levin, ED; Seidler, FJ
MLA Citation
Slotkin, TA, Skavicus, S, Card, J, Levin, ED, and Seidler, FJ. "Diverse neurotoxicants target the differentiation of embryonic neural stem cells into neuronal and glial phenotypes." Toxicology 372 (November 2, 2016): 42-51.
PMID
27816694
Source
epmc
Published In
TOXICOLOGY
Volume
372
Publish Date
2016
Start Page
42
End Page
51
DOI
10.1016/j.tox.2016.10.015

Reduction of nicotine self-administration by chronic nicotine infusion with H1 histamine blockade in female rats.

Chronic nicotine infusion via transdermal patches has been widely shown to assist with smoking cessation. In particular, transdermal nicotine treatment prior to quitting smoking helps reduce ad libitum smoking and aids cessation Rose et al. (Nicotine Tob Res 11:1067-75, 2009). However, despite this success, the majority of smokers who use transdermal nicotine fail to permanently quit smoking. Additional treatments are needed. Tobacco addiction does not just depend on nicotinic receptor systems; a variety of neural systems are involved, including dopamine, norepinepherine, serotonin, and histamine.Given the involvement of a variety of neural systems in the circuits of addiction, combination therapy may offer improved efficacy for successful smoking cessation beyond single treatments alone. We have found that pyrilamine, an H1 histamine antagonist, significantly decreases nicotine self-administration in rats.The current study was conducted to confirm the effect of chronic nicotine infusion on ongoing nicotine self-administration and resumed access after enforced abstinence and to determine the interaction of chronic nicotine with an H1 antagonist treatment.Chronic nicotine infusion via osmotic minipump (2.5 and 5 mg/kg/day for 28 days) significantly reduced nicotine self-administration in a dose-dependent manner. Chronic nicotine infusion also reduced the resumption of nicotine self-administration after enforced abstinence. Chronic pyrilamine infusion (25 mg/kg/day for 14 days) also significantly reduced nicotine self-administration.The combination of chronic nicotine and pyrilamine reduced nicotine self-administration to a greater extent than treatment with either drug alone.

Authors
Levin, ED; Hall, BJ; Chattopadhyay, A; Slade, S; Wells, C; Rezvani, AH; Rose, JE
MLA Citation
Levin, ED, Hall, BJ, Chattopadhyay, A, Slade, S, Wells, C, Rezvani, AH, and Rose, JE. "Reduction of nicotine self-administration by chronic nicotine infusion with H1 histamine blockade in female rats." Psychopharmacology 233.15-16 (August 2016): 3009-3015.
PMID
27318988
Source
epmc
Published In
Psychopharmacology
Volume
233
Issue
15-16
Publish Date
2016
Start Page
3009
End Page
3015
DOI
10.1007/s00213-016-4347-1

Cognitive and Behavioral Impairments Evoked by Low-Level Exposure to Tobacco Smoke Components: Comparison with Nicotine Alone.

Active maternal smoking has adverse effects on neurobehavioral development of the offspring, with nicotine (Nic) providing much of the underlying causative mechanism. To determine whether the lower exposures caused by second-hand smoke are deleterious, we administered tobacco smoke extract (TSE) to pregnant rats starting preconception and continued through the second postnatal week, corresponding to all 3 trimesters of fetal brain development. Dosing was adjusted to produce maternal plasma Nic concentrations encountered with second-hand smoke, an order of magnitude below those seen in active smokers. We then compared TSE effects to those of an equivalent dose of Nic alone, and to a 10-fold higher Nic dose. Gestational exposure to TSE and Nic significantly disrupted cognitive and behavioral function in behavioral tests given during adolescence and adulthood (postnatal weeks 4-40), producing hyperactivity, working memory deficits, and impairments in emotional processing, even at the low exposure levels corresponding to second-hand smoke. Although TSE effects were highly correlated with those of Nic, the effects of TSE were much larger than could be attributed to just the Nic in the mixture. Indeed, TSE effects more closely resembled those of the 10-fold higher Nic levels, but still exceeded their magnitude. In combination with our earlier findings, this study thus completes the chain of causation to prove that second-hand smoke exposure causes neurodevelopmental deficits, originating in disruption of neurodifferentiation, leading to miswiring of neuronal circuits, and as shown here, culminating in behavioral dysfunction. As low level exposure to Nic alone produced neurobehavioral teratology, 'harm reduction' Nic products do not abolish the potential for neurodevelopmental damage.

Authors
Hall, BJ; Cauley, M; Burke, DA; Kiany, A; Slotkin, TA; Levin, ED
MLA Citation
Hall, BJ, Cauley, M, Burke, DA, Kiany, A, Slotkin, TA, and Levin, ED. "Cognitive and Behavioral Impairments Evoked by Low-Level Exposure to Tobacco Smoke Components: Comparison with Nicotine Alone." Toxicological sciences : an official journal of the Society of Toxicology 151.2 (June 2016): 236-244.
PMID
26919958
Source
epmc
Published In
Toxicological Sciences (Elsevier)
Volume
151
Issue
2
Publish Date
2016
Start Page
236
End Page
244
DOI
10.1093/toxsci/kfw042

Crumbling Infrastructure and Learning Impairment: A Call for Responsibility.

Authors
Levin, ED
MLA Citation
Levin, ED. "Crumbling Infrastructure and Learning Impairment: A Call for Responsibility." Environmental health perspectives 124.5 (May 2016): A79-.
PMID
27136451
Source
epmc
Published In
Environmental health perspectives
Volume
124
Issue
5
Publish Date
2016
Start Page
A79
DOI
10.1289/ehp69

Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats.

D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that reacts with wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFRvIII proteins overexpressed in glioblastomas. This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and Drug Administration Investigational New Drug application. After the optimization of the formulation and administration, two cohorts (an acute and chronic cohort necropsied on study days 5 and 34) of Sprague-Dawley (SD) rats (four groups of 5 males and 5 females) were infused with the D2C7-IT formulation at total doses of 0, 0.05, 0.1, 0.4 μg (the acute cohort) and 0, 0.05, 0.1, 0.35 μg (the chronic cohort) for approximately 72 h by intracerebral convection-enhanced delivery using osmotic pumps. Mortality was observed in the 0.40 μg (5/10 rats) and 0.35 μg (4/10 rats) high-dose groups of each cohort. Body weight loss and abnormal behavior were only revealed in the rats treated with high doses of D2C7-IT. No dose-related effects were observed in clinical laboratory tests in either cohort. A gross pathologic examination of systemic tissues from the high-dose and control groups in both cohorts exhibited no dose-related or drug-related pathologic findings. Brain histopathology revealed the frequent occurrence of dose-related encephalomalacia, edema, and demyelination in the high-dose groups of both cohorts. In this study, the maximum tolerated dose of D2C7-IT was determined to be between 0.10 and 0.35 μg, and the no-observed-adverse-effect-level was 0.05 μg in SD rats. Both parameters were utilized to design the Phase I/II D2C7-IT clinical trial.

Authors
Bao, X; Chandramohan, V; Reynolds, RP; Norton, JN; Wetsel, WC; Rodriguiz, RM; Aryal, DK; McLendon, RE; Levin, ED; Petry, NA; Zalutsky, MR; Burnett, BK; Kuan, C-T; Pastan, IH; Bigner, DD
MLA Citation
Bao, X, Chandramohan, V, Reynolds, RP, Norton, JN, Wetsel, WC, Rodriguiz, RM, Aryal, DK, McLendon, RE, Levin, ED, Petry, NA, Zalutsky, MR, Burnett, BK, Kuan, C-T, Pastan, IH, and Bigner, DD. "Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats." Investigational new drugs 34.2 (April 2016): 149-158.
PMID
26728879
Source
epmc
Published In
Investigational New Drugs
Volume
34
Issue
2
Publish Date
2016
Start Page
149
End Page
158
DOI
10.1007/s10637-015-0318-3

Dextromethorphan interactions with histaminergic and serotonergic treatments to reduce nicotine self-administration in rats.

Combining effective treatments with diverse mechanisms of action for smoking cessation may provide better therapy by targeting multiple points of control in the neural circuits underlying addiction. Previous research in a rat model has shown that dextromethorphan, which has α3β4 nicotinic and NMDA glutamatergic antagonist actions, significantly decreases nicotine self-administration. We have found in the rat model that the H1 histamine antagonist pyrilamine and the serotonin 5HT2C agonist lorcaserin also significantly reduce nicotine self-administration. The current studies were conducted to determine the interactive effects of dextromethorphan with pyrilamine and lorcaserin on nicotine self-administration in rats. Young adult female rats were fitted with jugular IV catheters and trained to self-administer a nicotine infusion dose of 0.03-mg/kg/infusion. In an initial dose-effect function study of dextromethorphan, we found a monotonic decrease in nicotine self-administration over a dose range of 1 to 30-mg/kg with the lowest effective dose of 3-mg/kg. Then, with two separate cohorts of rats, dextromethorphan (0, 3.3, and 10-mg/kg) interactions with pyrilamine (0, 4.43, and 13.3-mg/kg) were investigated as well as interactions with lorcaserin (0, 0.3125 and 0.625-mg/kg). In the pyrilamine-dextromethorphan interaction study, an acute dose of pyrilamine (13.3-mg/kg) as well as an acute dose of dextromethorphan caused a significant decrease in nicotine self-administration. There were mutually augmenting effects of these two drugs. The combination of dextromethorphan (10-mg/kg) and pyrilamine (13.3-mg/kg) significantly lowered nicotine self-administration relative to either 10-mg/kg of dextromethorphan alone (p<0.05) or 13.3-mg/kg of pyrilamine alone (p<0.0005). In the lorcaserin-dextromethorphan study, an acute dose of lorcaserin (0.312-mg/kg) as well as an acute dose of dextromethorphan (10-mg/kg) caused a significant decrease in nicotine self-administration replicating previous findings. Augmenting interactions were observed with dextromethorphan and pyrilamine as well as lorcaserin. These findings suggest that combination therapy may be more effective smoking cessation treatments than monotherapy.

Authors
Briggs, SA; Hall, BJ; Wells, C; Slade, S; Jaskowski, P; Morrison, M; Rezvani, AH; Rose, JE; Levin, ED
MLA Citation
Briggs, SA, Hall, BJ, Wells, C, Slade, S, Jaskowski, P, Morrison, M, Rezvani, AH, Rose, JE, and Levin, ED. "Dextromethorphan interactions with histaminergic and serotonergic treatments to reduce nicotine self-administration in rats." Pharmacology, biochemistry, and behavior 142 (March 2016): 1-7.
PMID
26704812
Source
epmc
Published In
Pharmacology Biochemistry and Behavior
Volume
142
Publish Date
2016
Start Page
1
End Page
7
DOI
10.1016/j.pbb.2015.12.004

Persistent behavioral effects following early life exposure to retinoic acid or valproic acid in zebrafish.

Moderate to severe dysregulation in retinoid signaling during early development is associated with a constellation of physical malformations and/or neural tube defects, including spina bifida. It is thought that more subtle dysregulation of this system, which might be achievable via dietary (i.e. hypervitaminosis A) or pharmacological (i.e. valproic acid) exposure in humans, will manifest on behavioral domains including sociability, without overt physical abnormalities.During early life, zebrafish were exposed to low doses of two chemicals that disrupt retinoid signaling. From 0 to 5dpf, larvae were reared in aqueous solutions containing retinoic acid (0, 0.02, 0.2 or 2nM) or valproic acid (0, 0.5, 5.0 or 50μM). One cohort of zebrafish was assessed using a locomotor activity screen at 6-dpf; another was reared to adulthood and assessed using a neurobehavioral test battery (startle habituation, novel tank exploration, shoaling, and predator escape/avoidance).There was no significant increase in the incidence of physical malformation among exposed fish compared to controls. Both retinoic acid and valproic acid exposures during development disrupted larval activity with persisting behavioral alterations later in life, primarily manifesting as decreased social affiliation.Social behavior and some aspects of motor function were altered in exposed fish; the importance of examining emotional or psychological consequences of early life exposure to retinoid acting chemicals is discussed.

Authors
Bailey, JM; Oliveri, AN; Karbhari, N; Brooks, RAJ; De La Rocha, AJ; Janardhan, S; Levin, ED
MLA Citation
Bailey, JM, Oliveri, AN, Karbhari, N, Brooks, RAJ, De La Rocha, AJ, Janardhan, S, and Levin, ED. "Persistent behavioral effects following early life exposure to retinoic acid or valproic acid in zebrafish." Neurotoxicology 52 (January 2016): 23-33.
PMID
26439099
Source
epmc
Published In
NeuroToxicology
Volume
52
Publish Date
2016
Start Page
23
End Page
33
DOI
10.1016/j.neuro.2015.10.001

Developmental exposure to a complex PAH mixture causes persistent behavioral effects in naive Fundulus heteroclitus (killifish) but not in a population of PAH-adapted killifish.

Acute exposures to some individual polycyclic aromatic hydrocarbons (PAHs) and complex PAH mixtures are known to cause cardiac malformations and edema in the developing fish embryo. However, the heart is not the only organ impacted by developmental PAH exposure. The developing brain is also affected, resulting in lasting behavioral dysfunction. While acute exposures to some PAHs are teratogenically lethal in fish, little is known about the later life consequences of early life, lower dose subteratogenic PAH exposures. We sought to determine and characterize the long-term behavioral consequences of subteratogenic developmental PAH mixture exposure in both naive killifish and PAH-adapted killifish using sediment pore water derived from the Atlantic Wood Industries Superfund Site. Killifish offspring were embryonically treated with two low-level PAH mixture dilutions of Elizabeth River sediment extract (ERSE) (TPAH 5.04 μg/L and 50.4 μg/L) at 24h post fertilization. Following exposure, killifish were raised to larval, juvenile, and adult life stages and subjected to a series of behavioral tests including: a locomotor activity test (4 days post-hatch), a sensorimotor response tap/habituation test (3 months post hatch), and a novel tank diving and exploration test (3months post hatch). Killifish were also monitored for survival at 1, 2, and 5 months over 5-month rearing period. Developmental PAH exposure caused short-term as well as persistent behavioral impairments in naive killifish. In contrast, the PAH-adapted killifish did not show behavioral alterations following PAH exposure. PAH mixture exposure caused increased mortality in reference killifish over time; yet, the PAH-adapted killifish, while demonstrating long-term rearing mortality, had no significant changes in mortality associated with ERSE exposure. This study demonstrated that early embryonic exposure to PAH-contaminated sediment pore water caused long-term locomotor and behavioral alterations in killifish, and that locomotor alterations could be observed in early larval stages. Additionally, our study highlights the resistance to behavioral alterations caused by low-level PAH mixture exposure in the adapted killifish population. Furthermore, this is the first longitudinal behavioral study to use killifish, an environmentally important estuarine teleost fish, and this testing framework can be used for future contaminant assessment.

Authors
Brown, DR; Bailey, JM; Oliveri, AN; Levin, ED; Di Giulio, RT
MLA Citation
Brown, DR, Bailey, JM, Oliveri, AN, Levin, ED, and Di Giulio, RT. "Developmental exposure to a complex PAH mixture causes persistent behavioral effects in naive Fundulus heteroclitus (killifish) but not in a population of PAH-adapted killifish." Neurotoxicology and teratology 53 (January 2016): 55-63.
Website
http://hdl.handle.net/10161/12417
PMID
26548404
Source
epmc
Published In
Neurotoxicology and Teratology
Volume
53
Publish Date
2016
Start Page
55
End Page
63
DOI
10.1016/j.ntt.2015.10.007

Different Lines of Rats Selectively-Bred for High Alcohol-Drinking Demonstrate Disparate Preferences for Nicotine Self-Administration

Authors
Rezvani, AH; Levin, ED; Wells, C; Slade, S; Morrison, M; Marshall, L; Morris, M; Confino, J; Allenby, C; Lumeng, L
MLA Citation
Rezvani, AH, Levin, ED, Wells, C, Slade, S, Morrison, M, Marshall, L, Morris, M, Confino, J, Allenby, C, and Lumeng, L. "Different Lines of Rats Selectively-Bred for High Alcohol-Drinking Demonstrate Disparate Preferences for Nicotine Self-Administration." Journal of Drug and Alcohol Research 5 (2016): 1-9.
Website
http://hdl.handle.net/10161/13071
Source
crossref
Published In
Journal of drug and alcohol research
Volume
5
Publish Date
2016
Start Page
1
End Page
9
DOI
10.4303/jdar/235972

Neuro-anatomic mapping of dopamine D1 receptor involvement in nicotine self-administration in rats.

Dopaminergic signaling has long been known to be a critical factor in nicotine addiction, as well as other drugs of abuse. Dopaminergic projections from the VTA to the nucleus accumbens and prefrontal cortex have been well established to be critical to the reinforcing effects of these drugs. However, other projections of dopamine neurons are likely to have significant roles in this process. Also, the relative contributions of D1 and D2 dopamine receptors in drug addiction and its treatment remain to be fully understood. In this study, we examined the effects of blocking D1 and D2 receptors in the nucleus accumbens shell (AcS), anterior cingulate cortex (ACC), and parietal association cortex (PtA) on nicotine self-administration in rats. Female Sprague-Dawley rats were fitted with jugular catheters and allowed to self-administer nicotine (0.03 mg/kg/infusion) on an FR1 schedule. Rats were fitted with bilateral infusion cannulae to allow infusion of D1 or D2 antagonists (SCH-23390 or haloperidol) into each targeted brain area. Acute local infusions of SCH-23390 (1-4 μg/side) into the AcS and PtA significantly reduced nicotine self-administration by up to 75%. SCH-23390 infusion into the ACC was less effective with only suggestive non-significant reductions of nicotine self-administration. Acute, local infusions of haloperidol (0.5-2 μg/side) in any of the brain regions targeted did not have significant effects on nicotine self-administration. These results demonstrate a more significant role for D1 receptor mechanisms in the process of nicotine reinforcement and help provide a more detailed neuroanatomic map of nicotine dependence in the brain.

Authors
Hall, BJ; Slade, S; Allenby, C; Kutlu, MG; Levin, ED
MLA Citation
Hall, BJ, Slade, S, Allenby, C, Kutlu, MG, and Levin, ED. "Neuro-anatomic mapping of dopamine D1 receptor involvement in nicotine self-administration in rats." Neuropharmacology 99 (December 2015): 689-695.
PMID
25797492
Source
epmc
Published In
Neuropharmacology
Volume
99
Publish Date
2015
Start Page
689
End Page
695
DOI
10.1016/j.neuropharm.2015.03.005

Pharmacological analyses of learning and memory in zebrafish (Danio rerio).

Over the last decade, zebrafish (Danio rerio) have become valuable as a complementary model in behavioral pharmacology, opening a new avenue for understanding the relationships between drug action and behavior. This species offers a useful intermediate approach bridging the gap between in vitro studies and traditional mammalian models. Zebrafish offer great advantages of economy compared to their rodent counterparts, their complex brains and behavioral repertoire offer great translational potential relative to in vitro models. The development and validation of a variety of tests to measure behavior, including cognition, in zebrafish have set the stage for the use of this animal for behavioral pharmacology studies. This has led to research into the basic mechanisms of cognitive function as well as screening for potential cognition-improving drug therapies, among other lines of research. As with all models, zebrafish have limitations, which span pharmacokinetic challenges to difficulties quantifying behavior. The use, efficacy and limitations associated with a zebrafish model of cognitive function are discussed in this review, within the context of behavioral pharmacology.

Authors
Bailey, JM; Oliveri, AN; Levin, ED
MLA Citation
Bailey, JM, Oliveri, AN, and Levin, ED. "Pharmacological analyses of learning and memory in zebrafish (Danio rerio)." Pharmacology, biochemistry, and behavior 139 Pt B (December 2015): 103-111. (Review)
PMID
25792292
Source
epmc
Published In
Pharmacology Biochemistry and Behavior
Volume
139 Pt B
Publish Date
2015
Start Page
103
End Page
111
DOI
10.1016/j.pbb.2015.03.006

Perspectives on zebrafish neurobehavioral pharmacology.

Authors
Levin, ED; Kalueff, AV; Gerlai, RT
MLA Citation
Levin, ED, Kalueff, AV, and Gerlai, RT. "Perspectives on zebrafish neurobehavioral pharmacology." Pharmacology, biochemistry, and behavior 139 Pt B (December 2015): 93-.
PMID
26675808
Source
epmc
Published In
Pharmacology Biochemistry and Behavior
Volume
139 Pt B
Publish Date
2015
Start Page
93
DOI
10.1016/j.pbb.2015.11.007

Persisting effects of a PBDE metabolite, 6-OH-BDE-47, on larval and juvenile zebrafish swimming behavior.

Polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants that are widely detected in the environment, biota, and humans. In mammals, PBDEs can be oxidatively metabolized to form hydroxylated polybrominated diphenyl ethers (OH-BDEs). While studies have examined behavioral deficits or alterations induced by exposure to PBDEs in both rodents and fish, no study to date has explored behavioral effects from exposure to OH-BDEs, which have been shown to have greater endocrine disrupting potential compared to PBDEs. In the present study, zebrafish (Danio rerio) were exposed during embryonic and larval development (0-6 days post fertilization, dpf) to a PBDE metabolite, 6-hydroxy, 2,2',4,4' tetrabromodiphenyl ether (10-50 nM) and then examined for short and long-term behavioral effects. Exposed zebrafish tested as larvae (6 dpf) showed an altered swimming response to light-dark transitions, exhibiting hypoactivity in light periods compared to control fish. When fish exposed from 0-6 dpf were tested as juveniles (45 dpf), they showed an increased fear response and hyperactivity in response to tests of novel environment exploration and habituation learning. These results demonstrate that early life exposure to a PBDE metabolite can have immediate or later life (more than a month after exposure) effects on activity levels, habituation, and fear/anxiety.

Authors
Macaulay, LJ; Bailey, JM; Levin, ED; Stapleton, HM
MLA Citation
Macaulay, LJ, Bailey, JM, Levin, ED, and Stapleton, HM. "Persisting effects of a PBDE metabolite, 6-OH-BDE-47, on larval and juvenile zebrafish swimming behavior." Neurotoxicology and teratology 52.Pt B (November 2015): 119-126.
PMID
25979796
Source
epmc
Published In
Neurotoxicology and Teratology
Volume
52
Issue
Pt B
Publish Date
2015
Start Page
119
End Page
126
DOI
10.1016/j.ntt.2015.05.002

Learning about cognition risk with the radial-arm maze in the developmental neurotoxicology battery.

Cognitive dysfunction has been found in epidemiological studies to be among the most sensitive impairments associated with developmental exposure to a variety of environmental contaminants from heavy metals to polyhalogenated hydrocarbons and pesticides. These chemicals have been also shown to impair cognitive function after developmental exposure in experimental animal models. The radial-arm maze (RAM) has proven to be a sensitive and reliable way to assess both learning and memory in a variety of species, most often in rats and mice. The RAM is a very adaptable test method that takes advantage of rodents' instinct to explore new places in the environment to forage. That is, rodents do not need to be trained to run through the maze; they will normally do this from the initial session of testing. Training with differential reinforcement for arm choices provides a more rigorous test of learning and memory. The RAM is quite adaptable for assessing various aspects of cognition. Although the RAM has been mostly used to assess spatial learning and memory, it can be configured to assess non-spatial memory as well. Both working and reference memory can be easily distinguished. The RAM can be run with both appetitive (food reinforced) and aversive (water escape) motivators. The RAM has been found to be sensitive to a wide variety of developmental toxicants including heavy metals such as mercury and pesticides such as chlorpyrifos. There is an extremely rich literature especially with rats showing the effects of many types of brain lesions and drug effects so that the participation of a wide variety of neural systems in RAM performance is known. These systems, notably the hippocampus and frontal cortex, and acetylcholine and glutamate neurotransmitter systems, are the same neural systems that have been shown in humans to be critical for learning and memory. This considerably aids the interpretation of neurobehavioral toxicity studies.

Authors
Levin, ED
MLA Citation
Levin, ED. "Learning about cognition risk with the radial-arm maze in the developmental neurotoxicology battery." Neurotoxicology and teratology 52.Pt A (November 2015): 88-92.
PMID
26013674
Source
epmc
Published In
Neurotoxicology and Teratology
Volume
52
Issue
Pt A
Publish Date
2015
Start Page
88
End Page
92
DOI
10.1016/j.ntt.2015.05.007

Neurotoxicity of FireMaster 550® in zebrafish (Danio rerio): Chronic developmental and acute adolescent exposures.

FireMaster® 550 (FM 550) is the second most commonly used flame retardant (FR) product in consumer goods and has been detected in household dust samples. However, neurobehavioral effects associated with exposure have not been characterized in detail. We investigated the behavioral effects of FM 550 in zebrafish to facilitate the integration of the cellular and molecular effects of FM 550 with its behavioral consequences. The effects of developmental FM 550 exposure on zebrafish larvae swimming shortly after the end of exposure as well as the persisting effects of this exposure on adolescent behavior were studied. In addition, the acute effects of FM 550 on behavior with exposure during adolescence in zebrafish were studied.Developmental exposure to 0, 0.01, 0.1 or 1 mg/L of FM 550 via immersion spanned 0-5 days post fertilization, with larval testing on day 6 and adolescent testing on days 40-45. Acute adolescent (45 dpf) exposure was to 0, 1.0 or 3.0 mg/L of FM 550 via immersion, for 24 h, with testing 2 h or 1 week later. The vehicle condition was colony tank water with .0004% (developmental) or .0012% (adolescent) DMSO. Zebrafish behavior was characterized across several domains including learning, social affiliation, sensorimotor function, predator escape, and novel environment exploration.Persisting effects of developmental FM 550 exposure included a significant (p<0.01) reduction in social behavior among all dose groups. Acute FM 550 exposure during adolescence caused hypoactivity and reduced social behavior (p's<0.05) when the fish were tested 2 h after exposure. These effects were attenuated at the 1 week post exposure testing pointTaken together, these data indicate that FM 550 may cause persisting neurobehavioral alterations to social behavior in the absence of perturbations along other behavioral domains and that developmental exposure is more costly to the organism than acute adolescent exposure.

Authors
Bailey, JM; Levin, ED
MLA Citation
Bailey, JM, and Levin, ED. "Neurotoxicity of FireMaster 550® in zebrafish (Danio rerio): Chronic developmental and acute adolescent exposures." Neurotoxicology and teratology 52.Pt B (November 2015): 210-219.
PMID
26239867
Source
epmc
Published In
Neurotoxicology and Teratology
Volume
52
Issue
Pt B
Publish Date
2015
Start Page
210
End Page
219
DOI
10.1016/j.ntt.2015.07.001

Developmental exposure to organophosphate flame retardants causes behavioral effects in larval and adult zebrafish.

Organophosphate flame retardants (OPFRs) have grown in usage since concerns about the health effects of the previously used polybrominated flame retardants led to their being phased out. The potential for OPFRs to cause adverse health effects of their own is still unexamined. Because of their structural similarities to organophosphate pesticides, which have themselves been heavily researched and shown to be neurobehavioral teratogens, we investigated the possibility that developmental exposure to two OPFRs, triphenyl phosphate (TPHP), and tris(1,3-dichloroisopropyl)phosphate (TDCIPP) might lead to behavioral impairment across the lifespan, as has been observed with the organophosphate pesticide chlorpyrifos.Zebrafish were exposed to 0.03 or 0.3 μM of TPHP, TDCIPP, or chlorpyrifos from 0 to 5 days post fertilization. Vehicle control consisted of 0.03% solution of DMSO. At 6 days post fertilization, larvae were tested on a locomotor assay. Separate cohorts of 6 day old larvae that were not tested on the larval assay were allowed to grow to adulthood. At 12 weeks post fertilization, these adult zebrafish were tested on a battery of behavioral assays that included tests of novel environment exploration, startle habituation, social affiliation, and predator escape.Developmental exposure altered zebrafish behavior across the lifespan. Larval zebrafish exposed to the 0.03 μM doses of chlorpyrifos or TDCIPP exhibited significant (p<0.05) hyperactivity in the locomotor assay. Organophosphate exposure significantly (p<0.05) altered the time course of adult zebrafish behavior in the novel environment, startle habituation, and social affiliation assays. Predator escape behavior was significantly (p<0.05) reduced in fish exposed to the 0.3 μM dose of TDCIPP. Exposure also caused hyperactivity in adult fish, with fish exposed to the 0.3 μM dose of TDCIPP exhibiting significantly (p<0.05) elevated locomotor behavior in the novel environment assay.Early developmental exposure to OPFRs produced behavioral impairment that persisted into adulthood. These findings support broader research investigating the role of organophosphate compounds, including the OPFRs used here, in developmental neurotoxicity.

Authors
Oliveri, AN; Bailey, JM; Levin, ED
MLA Citation
Oliveri, AN, Bailey, JM, and Levin, ED. "Developmental exposure to organophosphate flame retardants causes behavioral effects in larval and adult zebrafish." Neurotoxicology and teratology 52.Pt B (November 2015): 220-227.
PMID
26344674
Source
epmc
Published In
Neurotoxicology and Teratology
Volume
52
Issue
Pt B
Publish Date
2015
Start Page
220
End Page
227
DOI
10.1016/j.ntt.2015.08.008

Amitifadine, a triple monoamine re-uptake inhibitor, reduces nicotine self-administration in female rats.

A wider diversity of drug treatments to aid smoking cessation is needed to help tailor the most efficacious treatment for different types of smokers. This study was conducted to determine whether amitifadine, which inhibits re-uptake of dopamine, norepinephrine and serotonin, would decrease nicotine self-administration at doses that do not cause adverse side effects. Adult female Sprague-Dawley rats were trained to self-administer nicotine intravenous (IV) and were given acute doses of amitifadine in a repeated measures counterbalanced design. Effects of amitifadine on locomotor activity and food motivated responding were also evaluated. Chronic amitifadine effects were also examined. The 30 mg/kg amitifadine dose significantly reduced nicotine self-administration. The 5 and 10 mg/kg doses reduced nicotine self-administration during the first 15 min of the session when the greatest amount of nicotine was self-administered. The 30 mg/kg amitifadine dose, but not the lower doses caused a significant reduction in locomotor activity averaged over the one-hour session and reduced food motivated responding. The 10 mg/kg dose caused hypoactivity at the beginning of the session, but 5 mg/kg did not cause any hypoactivity. The effects of chronic amitifadine treatment (10 mg/kg) over the course of 15 sessions was also determined. Amitifadine caused a significant reduction in nicotine self-administration, which was not seen to diminish over two consecutive weeks of treatment and a week after enforced abstinence. Amitifadine significantly reduced nicotine self-administration. This prompts further research to determine if amitifadine might be an effective treatment for smoking cessation.

Authors
Levin, ED; Wells, C; Johnson, JE; Rezvani, AH; Bymaster, FP; Rose, JE
MLA Citation
Levin, ED, Wells, C, Johnson, JE, Rezvani, AH, Bymaster, FP, and Rose, JE. "Amitifadine, a triple monoamine re-uptake inhibitor, reduces nicotine self-administration in female rats." European journal of pharmacology 764 (October 2015): 30-37.
PMID
26101069
Source
epmc
Published In
European Journal of Pharmacology
Volume
764
Publish Date
2015
Start Page
30
End Page
37
DOI
10.1016/j.ejphar.2015.06.041

Nicotinic treatments not only for tobacco, but also other addictions

Authors
Levin, ED; Rezvani, AH; Xiao, Y; Yenugonda, VM; Brown, ML; Kellar, KJ
MLA Citation
Levin, ED, Rezvani, AH, Xiao, Y, Yenugonda, VM, Brown, ML, and Kellar, KJ. "Nicotinic treatments not only for tobacco, but also other addictions." October 2015.
Source
crossref
Published In
Biochemical Pharmacology
Volume
97
Issue
4
Publish Date
2015
Start Page
635
End Page
635
DOI
10.1016/j.bcp.2015.08.040

Teratogenic, bioenergetic, and behavioral effects of exposure to total particulate matter on early development of zebrafish (Danio rerio) are not mimicked by nicotine.

Cigarette smoke has been associated with a number of pathologies; however, the mechanisms leading to developmental effects are yet to be fully understood. The zebrafish embryo is regarded as a 'bridge model'; however, not many studies examined its applicability to cigarette smoke toxicity. This study examined the effects of total particulate matter (TPM) from 3R4F reference cigarettes on the early development of zebrafish (Danio rerio). Zebrafish embryos were exposed to two concentrations of TPM (0.4 and 1.4 μg/mL equi-nicotine units) or nicotine at equivalent doses. The exposures began at 2h post-fertilization (hpf) and lasted until 96 hpf. Several physiological parameters were assessed during or after the exposure. We show that TPM increased mortality, delayed hatching, and increased the incidence of deformities in zebrafish. TPM exposure also increased the incidence of hemorrhage and disrupted the angiogenesis of the major vessels in the brain. Moreover, TPM exposure reduced the larval body length, decreased the heart rate, and reduced the metabolic rate. Biomarkers of xenobiotic metabolism and oxidative stress were also affected. TPM-exposed zebrafish also differed behaviorally: at 24 hpf the embryos had a higher frequency of spontaneous contractions and at 144 hpf the larvae displayed swimming hyperactivity. This study demonstrates that TPM disrupts several aspects of early development in zebrafish. The effects reported for TPM were not attributable to nicotine, since embryos treated with nicotine alone did not differ significantly from the control group. Collectively, our work illustrates the utility of zebrafish as an alternative model to evaluate the toxic effects of cigarette smoke constituents.

Authors
Massarsky, A; Jayasundara, N; Bailey, JM; Oliveri, AN; Levin, ED; Prasad, GL; Di Giulio, RT
MLA Citation
Massarsky, A, Jayasundara, N, Bailey, JM, Oliveri, AN, Levin, ED, Prasad, GL, and Di Giulio, RT. "Teratogenic, bioenergetic, and behavioral effects of exposure to total particulate matter on early development of zebrafish (Danio rerio) are not mimicked by nicotine." Neurotoxicology and teratology 51 (September 18, 2015): 77-88.
PMID
26391568
Source
epmc
Published In
Neurotoxicology and Teratology
Volume
51
Publish Date
2015
Start Page
77
End Page
88
DOI
10.1016/j.ntt.2015.09.006

Developmental Neurotoxicity of Tobacco Smoke Directed Toward Cholinergic and Serotonergic Systems: More Than Just Nicotine.

Tobacco smoke contains thousands of compounds in addition to nicotine, a known neuroteratogen. We evaluated the developmental neurotoxicity of tobacco smoke extract (TSE) administered to pregnant rats starting preconception and continued through the second postnatal week. We simulated nicotine concentrations encountered with second-hand smoke, an order of magnitude below those seen in active smokers, and compared TSE with an equivalent dose of nicotine alone, and to a 10-fold higher nicotine dose. We conducted longitudinal evaluations in multiple brain regions, starting in adolescence (postnatal day 30) and continued to full adulthood (day 150). TSE exposure impaired presynaptic cholinergic activity, exacerbated by a decrement in nicotinic cholinergic receptor concentrations. Although both nicotine doses produced presynaptic cholinergic deficits, these were partially compensated by hyperinnervation and receptor upregulation, effects that were absent with TSE. TSE also produced deficits in serotonin receptors in females that were not seen with nicotine. Regression analysis showed a profound sex difference in the degree to which nicotine could account for overall TSE effects: whereas the 2 nicotine doses accounted for 36%-46% of TSE effects in males, it accounted for only 7%-13% in females. Our results show that the adverse effects of TSE on neurodevelopment exceed those that can be attributed to just the nicotine present in the mixture, and further, that the sensitivity extends down to levels commensurate with second-hand smoke exposure. Because nicotine itself evoked deficits at low exposures, "harm reduction" nicotine products do not eliminate the potential for neurodevelopmental damage.

Authors
Slotkin, TA; Skavicus, S; Card, J; Stadler, A; Levin, ED; Seidler, FJ
MLA Citation
Slotkin, TA, Skavicus, S, Card, J, Stadler, A, Levin, ED, and Seidler, FJ. "Developmental Neurotoxicity of Tobacco Smoke Directed Toward Cholinergic and Serotonergic Systems: More Than Just Nicotine." Toxicological sciences : an official journal of the Society of Toxicology 147.1 (September 2015): 178-189.
PMID
26085346
Source
epmc
Published In
Toxicological Sciences (Elsevier)
Volume
147
Issue
1
Publish Date
2015
Start Page
178
End Page
189
DOI
10.1093/toxsci/kfv123

Role of nicotinic receptors in the lateral habenula in the attenuation of amphetamine-induced prepulse inhibition deficits of the acoustic startle response in rats.

Prepulse inhibition (PPI) refers to the reduction of the startle response magnitude when a startling stimulus is closely preceded by a weak stimulus. PPI is commonly used to measure sensorimotor gating. In rats, the PPI reduction induced by the dopamine agonist apomorphine can be reversed by systemic administration of nicotine. A high concentration of nicotinic receptors is found in the lateral habenula (LHb), an epithalamic structure with efferent projections to brain regions involved in the modulation of PPI, which has been shown to regulate the activity of midbrain dopamine neurons.The prospective role of nicotinic receptors in the LHb in the regulation of PPI was assessed in this study, using different pharmacological models of sensorimotor gating deficits.Interactions between systemic amphetamine and haloperidol and intra-LHb infusions of mecamylamine (10 μg/side) or nicotine (30 μg/side) on PPI were analyzed in Experiments 1 and 2. Intra-LHb infusions of different nicotine doses (25, and 50 μg/side) and their interactions with systemic administration of amphetamine or dizocilpine on PPI were examined in Experiments 3 and 4.Infusions of nicotine into the LHb dose-dependently attenuated amphetamine-induced PPI deficits but had no effect on PPI disruptions caused by dizocilpine. Intra-LHb mecamylamine infusions did not affect PPI nor interact with dopaminergic manipulations.These results are congruent with previous reports of systemic nicotine effects on PPI, suggesting a role of the LHb in the attenuation of sensorimotor gating deficits caused by the hyperactivity of dopamine systems.

Authors
Larrauri, JA; Burke, DA; Hall, BJ; Levin, ED
MLA Citation
Larrauri, JA, Burke, DA, Hall, BJ, and Levin, ED. "Role of nicotinic receptors in the lateral habenula in the attenuation of amphetamine-induced prepulse inhibition deficits of the acoustic startle response in rats." Psychopharmacology 232.16 (August 2015): 3009-3017.
PMID
25912180
Source
epmc
Published In
Psychopharmacology
Volume
232
Issue
16
Publish Date
2015
Start Page
3009
End Page
3017
DOI
10.1007/s00213-015-3940-z

Amelioration strategies fail to prevent tobacco smoke effects on neurodifferentiation: Nicotinic receptor blockade, antioxidants, methyl donors.

Tobacco smoke exposure is associated with neurodevelopmental disorders. We used neuronotypic PC12 cells to evaluate the mechanisms by which tobacco smoke extract (TSE) affects neurodifferentiation. In undifferentiated cells, TSE impaired DNA synthesis and cell numbers to a much greater extent than nicotine alone; TSE also impaired cell viability to a small extent. In differentiating cells, TSE enhanced cell growth at the expense of cell numbers and promoted emergence of the dopaminergic phenotype. Nicotinic receptor blockade with mecamylamine was ineffective in preventing the adverse effects of TSE and actually enhanced the effect of TSE on the dopamine phenotype. A mixture of antioxidants (vitamin C, vitamin E, N-acetyl-l-cysteine) provided partial protection against cell loss but also promoted loss of the cholinergic phenotype in response to TSE. Notably, the antioxidants themselves altered neurodifferentiation, reducing cell numbers and promoting the cholinergic phenotype at the expense of the dopaminergic phenotype, an effect that was most prominent for N-acetyl-l-cysteine. Treatment with methyl donors (vitamin B12, folic acid, choline) had no protectant effect and actually enhanced the cell loss evoked by TSE; they did have a minor, synergistic interaction with antioxidants protecting against TSE effects on growth. Thus, components of tobacco smoke perturb neurodifferentiation through mechanisms that cannot be attributed to the individual effects of nicotine, oxidative stress or interference with one-carbon metabolism. Consequently, attempted amelioration strategies may be partially effective at best, or, as seen here, can actually aggravate injury by interfering with normal developmental signals and/or by sensitizing cells to TSE effects on neurodifferentiation.

Authors
Slotkin, TA; Skavicus, S; Card, J; Levin, ED; Seidler, FJ
MLA Citation
Slotkin, TA, Skavicus, S, Card, J, Levin, ED, and Seidler, FJ. "Amelioration strategies fail to prevent tobacco smoke effects on neurodifferentiation: Nicotinic receptor blockade, antioxidants, methyl donors." Toxicology 333 (July 2015): 63-75.
PMID
25891525
Source
epmc
Published In
TOXICOLOGY
Volume
333
Publish Date
2015
Start Page
63
End Page
75
DOI
10.1016/j.tox.2015.04.005

Neurobehavioral impairments caused by developmental imidacloprid exposure in zebrafish.

Neonicotinoid insecticides are becoming more widely applied as organophosphate (OP) insecticides are decreasing in use. Because of their relative specificity to insect nicotinic receptors, they are thought to have reduced risk of neurotoxicity in vertebrates. However, there is scant published literature concerning the neurobehavioral effects of developmental exposure of vertebrates to neonicotinoids.Using zebrafish, we investigated the neurobehavioral effects of developmental exposure to imidacloprid, a prototypic neonicotinoid pesticide. Nicotine was also administered for comparison. Zebrafish were exposed via immersion in aqueous solutions containing 45 μM or 60 μM of imidacloprid or nicotine (or vehicle control) from 4h to 5d post fertilization. The functional effects of developmental exposure to both imidacloprid and nicotine were assessed in larvae using an activity assay and during adolescence and adulthood using a battery of neurobehavioral assays, including assessment of sensorimotor response and habituation in a tactile startle test, novel tank swimming, and shoaling behavior.In larvae, developmental imidacloprid exposure at both doses significantly decreased swimming activity. The 5D strains of zebrafish were more sensitive to both nicotine and imidacloprid than the AB* strain. In adolescent and adult fish, developmental exposure to imidacloprid significantly decreased novel tank exploration and increased sensorimotor response to startle stimuli. While nicotine did not affect novel tank swimming, it increased sensorimotor response to startle stimuli at the low dose. No effects of either compound were found on shoaling behavior or habituation to a startling stimulus.Early developmental exposure to imidacloprid has both early-life and persisting effects on neurobehavioral function in zebrafish. Its developmental neurotoxicity should be further investigated.

Authors
Crosby, EB; Bailey, JM; Oliveri, AN; Levin, ED
MLA Citation
Crosby, EB, Bailey, JM, Oliveri, AN, and Levin, ED. "Neurobehavioral impairments caused by developmental imidacloprid exposure in zebrafish." Neurotoxicology and teratology 49 (May 2, 2015): 81-90.
PMID
25944383
Source
epmc
Published In
Neurotoxicology and Teratology
Volume
49
Publish Date
2015
Start Page
81
End Page
90
DOI
10.1016/j.ntt.2015.04.006

Low dose tobacco smoke extract exposure during development causes long-term behavioral dysfunction in rats

Authors
Hall, BJ; Cauley, M; Kiany, A; Burke, DA; Levin, ED
MLA Citation
Hall, BJ, Cauley, M, Kiany, A, Burke, DA, and Levin, ED. "Low dose tobacco smoke extract exposure during development causes long-term behavioral dysfunction in rats." May 2015.
Source
crossref
Published In
Neurotoxicology and Teratology
Volume
49
Publish Date
2015
Start Page
121
End Page
122
DOI
10.1016/j.ntt.2015.04.073

The neurobehavioral toxicity of FireMaster 550® in zebrafish (Danio rerio): Chronic developmental and acute adolescent exposures

Authors
Bailey, J; Levin, E
MLA Citation
Bailey, J, and Levin, E. "The neurobehavioral toxicity of FireMaster 550® in zebrafish (Danio rerio): Chronic developmental and acute adolescent exposures." May 2015.
Source
crossref
Published In
Neurotoxicology and Teratology
Volume
49
Publish Date
2015
Start Page
118
End Page
118
DOI
10.1016/j.ntt.2015.04.064

Early-life exposure to organophosphate flame retardants alters behavior in adult zebrafish: A comparison with organophosphate pesticides

Authors
Oliveri, A; Levin, E
MLA Citation
Oliveri, A, and Levin, E. "Early-life exposure to organophosphate flame retardants alters behavior in adult zebrafish: A comparison with organophosphate pesticides." May 2015.
Source
crossref
Published In
Neurotoxicology and Teratology
Volume
49
Publish Date
2015
Start Page
130
End Page
130
DOI
10.1016/j.ntt.2015.04.096

Age and sex differences in starting nicotine self-administration in early, mid or late adolescence vs. adulthood: Cause and effect relationships determined in a rat model

Authors
Levin, ED
MLA Citation
Levin, ED. "Age and sex differences in starting nicotine self-administration in early, mid or late adolescence vs. adulthood: Cause and effect relationships determined in a rat model." May 2015.
Source
crossref
Published In
Neurotoxicology and Teratology
Volume
49
Publish Date
2015
Start Page
140
End Page
140
DOI
10.1016/j.ntt.2015.04.128

Bupropion-varenicline interactions and nicotine self-administration behavior in rats.

Varenicline and bupropion each have been shown to significantly improve cessation of tobacco addiction in humans. They act through different mechanisms and the question about the potential added efficacy with their combined used has arisen. Preclinical animal models of nicotine addiction can help with the evaluation of this combined approach and what dose combinations of varenicline and bupropion may be useful for enhancing tobacco cessation. In this study, we investigated the interacting dose-effect functions of varenicline and bupropion in a rat model of nicotine self-administration. Young adult female Sprague-Dawley rats were allowed to self-administer nicotine in 1-h sessions under an FR1 reinforcement schedule. Varenicline (0.3, 1. 3 mg/kg) and bupropion (8.33, 25, 75 mg/kg) were administered alone or together 15 min before each session. The vehicle saline was the control. Higher doses of each drug alone reduced nicotine self-administration compared to control with reductions of 62% and 75% with 3 mg/kg varenicline and 75 mg/kg bupropion respectively. Lower dose varenicline which does not by itself reduce nicotine self-administration, significantly augmented bupropion effects. The 0.3 mg/kg varenicline dose combined with the 25 and 75 mg/kg bupropion doses caused greater reductions of nicotine self-administration than either dose of bupropion given alone. However, higher dose varenicline did not have this effect. Lower dose bupropion did not augment varenicline effects. Only the high bupropion dose significantly enhanced the varenicline effect. Likewise, combining 1 mg/kg varenicline with 75 mg/kg bupropion reduced self-administration to a greater extent than either dose alone. These results demonstrate that combination therapy with varenicline and bupropion may be more beneficial than monotherapy with either drug alone.

Authors
Hall, BJ; Slade, S; Wells, C; Rose, JE; Levin, ED
MLA Citation
Hall, BJ, Slade, S, Wells, C, Rose, JE, and Levin, ED. "Bupropion-varenicline interactions and nicotine self-administration behavior in rats." Pharmacology, biochemistry, and behavior 130 (March 2015): 84-89.
PMID
25616031
Source
epmc
Published In
Pharmacology Biochemistry and Behavior
Volume
130
Publish Date
2015
Start Page
84
End Page
89
DOI
10.1016/j.pbb.2015.01.009

Long-term behavioral impairment following acute embryonic ethanol exposure in zebrafish.

Developmental exposure to ethanol has long been known to cause persisting neurobehavioral impairment. However, the neural and behavioral mechanisms underlying these deficits and the importance of exposure timing are not well-characterized. Given the importance of timing and sequence in neurodevelopment it would be expected that alcohol intoxication at different developmental periods would result in distinct neurobehavioral consequences.Zebrafish embryos were exposed to ethanol (0%, 1%, 3%) at either 8-10 or 24-27 h post-fertilization (hpf) then reared to adolescence and evaluated on several behavioral endpoints. Habituation to a repeated environmental stimulus and overall sensorimotor function were assessed using a tap startle test; measurements of anxiety and exploration behavior were made following introduction to a novel tank; and spatial discrimination learning was assessed using aversive control in a three-chambered apparatus. Overt signs of dysmorphogenesis were also scored (i.e. craniofacial malformations, including eye diameter and midbrain-hindbrain boundary morphology).Ethanol treated fish were more active both at baseline and following a tap stimulus compared to the control fish and were hyperactive when placed in a novel tank. These effects were more prominent following exposure at 24-27 hpf than with the earlier exposure window, for both dose groups. Increases in physical malformation were only present in the 3% ethanol group; all malformed fish were excluded from behavioral testing.These results suggest specific domains of behavior are affected following ethanol exposure, with some but not all of the tests revealing significant impairment. The behavioral phenotypes following distinct exposure windows described here can be used to help link cellular and molecular mechanisms of developmental ethanol exposure to functional neurobehavioral effects.

Authors
Bailey, JM; Oliveri, AN; Zhang, C; Frazier, JM; Mackinnon, S; Cole, GJ; Levin, ED
MLA Citation
Bailey, JM, Oliveri, AN, Zhang, C, Frazier, JM, Mackinnon, S, Cole, GJ, and Levin, ED. "Long-term behavioral impairment following acute embryonic ethanol exposure in zebrafish." Neurotoxicology and teratology 48 (March 2015): 1-8.
PMID
25599606
Source
epmc
Published In
Neurotoxicology and Teratology
Volume
48
Publish Date
2015
Start Page
1
End Page
8
DOI
10.1016/j.ntt.2015.01.005

Prenatal nicotine changes the response to postnatal chlorpyrifos: Interactions targeting serotonergic synaptic function and cognition.

Nicotine and chlorpyrifos are developmental neurotoxicants that target serotonin systems. We examined whether prenatal nicotine exposure alters the subsequent response to chlorpyrifos given postnatally. Pregnant rats received nicotine throughout gestation at 3mg/kg/day, a regimen designed to achieve plasma levels seen in smokers; chlorpyrifos was given to pups on postnatal days (PN) 1-4 at 1mg/kg, just above the detection threshold for brain cholinesterase inhibition. We assessed long-term effects from adolescence (PN30) through full adulthood (PN150), measuring the expression of serotonin receptors and serotonin turnover (index of presynaptic impulse activity) in cerebrocortical brain regions encompassing the projections that are known targets for nicotine and chlorpyrifos. Nicotine or chlorpyrifos individually increased the expression of serotonin receptors, with greater effects on males than on females and with distinct temporal and regional patterns indicative of adaptive synaptic changes rather than simply an extension of initial injury. This interpretation was confirmed by our finding an increase in serotonin turnover, connoting presynaptic serotonergic hyperactivity. Animals receiving the combined treatment showed a reduction in these adaptive effects on receptor binding and turnover relative to the individual agents, or even an effect in the opposite direction; further, normal sex differences in serotonin receptor concentrations were dissipated or reversed, an effect that was confirmed by behavioral evaluations in the Novel Objection Recognition Test. In addition to the known liabilities associated with maternal smoking during pregnancy, our results point to additional costs in the form of heightened vulnerability to neurotoxic chemicals encountered later in life.

Authors
Slotkin, TA; Skavicus, S; Levin, ED; Seidler, FJ
MLA Citation
Slotkin, TA, Skavicus, S, Levin, ED, and Seidler, FJ. "Prenatal nicotine changes the response to postnatal chlorpyrifos: Interactions targeting serotonergic synaptic function and cognition." Brain research bulletin 111 (February 2015): 84-96.
PMID
25592617
Source
epmc
Published In
Brain Research Bulletin
Volume
111
Publish Date
2015
Start Page
84
End Page
96
DOI
10.1016/j.brainresbull.2015.01.003

Heterogeneity across brain regions and neurotransmitter interactions with nicotinic effects on memory function.

Nicotinic acetylcholine receptors have been shown in many studies to be critically involved in memory function. The precise roles these receptors play depend on the receptor subtype, their anatomic localization, their interactions with other parts of the neural systems underlying cognition and the particular domain of cognitive function. Nicotinic agonists can significantly improve learning, memory, and attention. Nicotinic receptors in the hippocampus are innervated by cholinergic projections from the medial septum and diagonal band. Local infusions of either α7 or α4β2 nicotinic antagonists into either the dorsal or ventral hippocampus produce amnestic effects in rats navigating about a radial arm maze. There is cholinergic innervation of nicotinic receptors in other components of the limbic system as well. In the basolateral amygdala and the anterior thalamus, similar amnestic effects of nicotinic α7 and α4β2 antagonists are seen. Interestingly, there are no additive amnestic effects observed in these limbic areas when α7 and α4β2 receptor antagonists are combined. The particular expression patterns of α7 and α4β2 nicotinic receptors in these limbic and cortical areas may explain this nonadditivity, but further research is needed to determine the specific cause of this phenomenon. Nicotinic receptor mechanisms in the limbic system play an important role in cognitive impairment for a variety of neurological disorders, including Alzheimer's disease and schizophrenia. Alzheimer's disease results in a dramatic decrease in hippocampal nicotinic receptor density, affecting α4β2 receptor expression most prominently. In schizophrenia, there are anomalies in α7 nicotinic receptor expression, which seem to be crucial for the cognitive impairment of the disorder. Chronic nicotine exposure, such as seen with tobacco use, results in an increase in nicotinic receptor density in the limbic system. This effect appears to be related to the desensitization of nicotinic receptors seen after agonist application. Open questions remain concerning the role of desensitization versus activation of nicotinic receptors in cognitive improvement.

Authors
Levin, ED; Hall, BJ; Rezvani, AH
MLA Citation
Levin, ED, Hall, BJ, and Rezvani, AH. "Heterogeneity across brain regions and neurotransmitter interactions with nicotinic effects on memory function." Current topics in behavioral neurosciences 23 (January 2015): 87-101.
PMID
25655888
Source
epmc
Published In
Current Topics in Behavioral Neurosciences
Volume
23
Publish Date
2015
Start Page
87
End Page
101
DOI
10.1007/978-3-319-13665-3_4

Persisting effects of a PBDE metabolite, 6-OH-BDE-47, on larval and juvenile zebrafish swimming behavior

Authors
Macaulay, LJ; Bailey, JM; Levin, ED; Stapleton, HM
MLA Citation
Macaulay, LJ, Bailey, JM, Levin, ED, and Stapleton, HM. "Persisting effects of a PBDE metabolite, 6-OH-BDE-47, on larval and juvenile zebrafish swimming behavior." NEUROTOXICOLOGY AND TERATOLOGY 52 (2015): 119-126.
Source
wos-lite
Published In
Neurotoxicology and Teratology
Volume
52
Publish Date
2015
Start Page
119
End Page
126
DOI
10.1016/j.ntr.2015.05.002

Assessment of pregnenolone effects on alcohol intake and preference in male alcohol preferring (P) rats

Authors
Rezvani, AH; Levin, ED
MLA Citation
Rezvani, AH, and Levin, ED. "Assessment of pregnenolone effects on alcohol intake and preference in male alcohol preferring (P) rats." EUROPEAN JOURNAL OF PHARMACOLOGY 740 (October 5, 2014): 53-57.
Source
wos-lite
Published In
European Journal of Pharmacology
Volume
740
Publish Date
2014
Start Page
53
End Page
57
DOI
10.1016/j.ejphar.2014.07.003

IV nicotine self-administration in rats using a consummatory operant licking response: sensitivity to serotonergic, glutaminergic and histaminergic drugs.

Tobacco smoking is characterized by repeated self-administration of nicotine by placing the cigarette in the mouth. The repeated hand-to-mouth self-administration is essentially a consummatory act. We recently developed a paradigm in which rats lick one of two spouts to trigger intravenous (IV) delivery of nicotine, which combines a consummatory act with rapid delivery of nicotine to model the act of tobacco smoking. We have found that rats will lick hundreds of times per nicotine infusion. In the current study, using the operant licking nicotine self-administration model with young adult Sprague-Dawley rats (0.03mg/kg/infusion of nicotine), we tested the effect of antagonists of H1 histamine receptors pyrilamine, serotonin (5HT) type 2 receptors ketanserin and N-methyl-d-aspartate (NMDA) glutamate receptors with d-cycloserine as well as an agonist of 5HT2c receptors lorcaserin, in dose ranges that we have found in previous studies to significantly reduce IV nicotine self-administration with the operant lever press operand. The H1 antagonist pyrilamine significantly reduced operant licking for nicotine self-administration. Pyrilamine caused significant reductions in the operant licking paradigm at lower doses (10 and 20mg/kg) than those we previously observed to affect responding in the operant lever press paradigm. In contrast, the 5HT2A and C antagonist ketanserin did not show an effect of reducing nicotine self-administration in the same dose range we had found in a previous study to significantly reduce operant lever press nicotine self-administration. The 5HT2C agonist lorcaserin significantly decreased nicotine self-administration in the licking paradigm at the same dose threshold as with lever press responding. The NMDA glutamate partial agonist d-cycloserine did not produce any change in nicotine self-administration with the licking operand, in contrast to its effect on the classic lever-pressing task. The rat model incorporating consummatory aspects of tobacco addiction can provide distinct and potentially more relevant information concerning possible new avenues of treatment to combat tobacco addiction.

Authors
Cousins, V; Rose, JE; Levin, ED
MLA Citation
Cousins, V, Rose, JE, and Levin, ED. "IV nicotine self-administration in rats using a consummatory operant licking response: sensitivity to serotonergic, glutaminergic and histaminergic drugs." Progress in neuro-psychopharmacology & biological psychiatry 54 (October 2014): 200-205.
PMID
24953434
Source
epmc
Published In
Progress in Neuro-Psychopharmacology & Biological Psychiatry
Volume
54
Publish Date
2014
Start Page
200
End Page
205
DOI
10.1016/j.pnpbp.2014.06.004

Decreasing nicotinic receptor activity and the spatial learning impairment caused by the NMDA glutamate antagonist dizocilpine in rats.

Nicotinic systems have been shown by a variety of studies to be involved in cognitive function. Nicotinic receptors have an inherent property to become desensitized after activation. The relative role of nicotinic receptor activation vs. net receptor inactivation by desensitization in the cognitive effects of nicotinic drugs remains to be fully understood. In these studies, we tested the effects of the α7 nicotinic receptor antagonist methyllycaconitine (MLA), the α4β2 nicotinic receptor antagonist dihydro-β-erythroidine (DHβE), the nonspecific nicotinic channel blocker mecamylamine and the α4β2 nicotinic receptor desensitizing agent sazetidine-A on learning in a repeated acquisition test. Adult female Sprague-Dawley rats were trained on a repeated acquisition learning procedure in an 8-arm radial maze. MLA (1-4mg/kg), DHβE (1-4mg/kg), mecamylamine (0.125-0.5mg/kg) or sazetidine-A (1 and 3mg/kg) were administered in four different studies either alone or together with the NMDA glutamate antagonist dizocilpine (0.05 and 0.10mg/kg). MLA significantly counteracted the learning impairment caused by dizocilpine. The overall choice accuracy impairment caused by dizocilpine was significantly attenuated by co-administration of DHβE. Low doses of the non-specific nicotinic antagonist mecamylamine also reduced dizocilpine-induced repeated acquisition impairment. Sazetidine-A reversed the accuracy impairment caused by dizocilpine. These studies provide evidence that a net decrease in nicotinic receptor activity can improve learning by attenuating learning impairment induced by NMDA glutamate blockade. This adds to evidence in cognitive tests that nicotinic antagonists can improve cognitive function. Further research characterizing the efficacy and mechanisms underlying nicotinic antagonist and desensitization induced cognitive improvement is warranted.

Authors
Burke, DA; Heshmati, P; Kholdebarin, E; Levin, ED
MLA Citation
Burke, DA, Heshmati, P, Kholdebarin, E, and Levin, ED. "Decreasing nicotinic receptor activity and the spatial learning impairment caused by the NMDA glutamate antagonist dizocilpine in rats." European journal of pharmacology 741 (October 2014): 132-139.
PMID
25064338
Source
epmc
Published In
European Journal of Pharmacology
Volume
741
Publish Date
2014
Start Page
132
End Page
139
DOI
10.1016/j.ejphar.2014.07.030

Effects of tobacco smoke constituents, anabasine and anatabine, on memory and attention in female rats.

Nicotine has been well characterized to improve memory and attention. Nicotine is the primary, but not only neuroactive compound in tobacco. Other tobacco constituents such as anabasine and anatabine also have agonist actions on nicotinic receptors. The current study investigated the effects of anabasine and anatabine on memory and attention. Adult female Sprague-Dawley rats were trained on a win-shift spatial working and reference memory task in the 16-arm radial maze or a visual signal detection operant task to test attention. Acute dose-effect functions of anabasine and anatabine over two orders of magnitude were evaluated for both tasks. In the radial-arm maze memory test, anabasine but not anatabine significantly reduced the memory impairment caused by the NMDA antagonist dizocilpine (MK-801). In the signal detection attentional task, anatabine but not anabasine significantly attenuated the attentional impairment caused by dizocilpine. These studies show that non-nicotine nicotinic agonists in tobacco, similar to nicotine, can significantly improve memory and attentional function. Both anabasine and anatabine produced cognitive improvement, but their effectiveness differed with regard to memory and attention. Follow-up studies with anabasine and anatabine are called for to determine their efficacy as therapeutics for memory and attentional dysfunction.

Authors
Levin, ED; Hao, I; Burke, DA; Cauley, M; Hall, BJ; Rezvani, AH
MLA Citation
Levin, ED, Hao, I, Burke, DA, Cauley, M, Hall, BJ, and Rezvani, AH. "Effects of tobacco smoke constituents, anabasine and anatabine, on memory and attention in female rats." Journal of psychopharmacology (Oxford, England) 28.10 (October 2014): 915-922.
PMID
25122040
Source
epmc
Published In
Journal of Psychopharmacology
Volume
28
Issue
10
Publish Date
2014
Start Page
915
End Page
922
DOI
10.1177/0269881114543721

Lorcaserin, a selective 5-HT(2C) receptor agonist, decreases alcohol intake in female alcohol preferring rats.

Serotonergic systems in the brain have been found to be important in the addiction to alcohol. The purpose of this study was to evaluate the efficacy of a novel 5-HT2c receptor agonist, lorcaserin for reducing alcohol consumption in alcohol-preferring (P) rats. Adult female rats were allowed to drink water or alcohol (12%, v/v) using a standard two-bottle choice procedure. Once stable baselines were established, the acute (0, 0.3125, 0.625 and 1.25 mg/kg, s.c.), and chronic (0, 0.625 mg/kg, sc for 10 days) effects of lorcaserin on alcohol intake and preference were assessed at different time points. In a separate experiment, the effects of lorcaserin on locomotor activity were determined. Our results show that both 0.625 and 1.25 mg/kg lorcaserin significantly reduced alcohol intake at 2, 4 and 6 h. after the drug administration. The chronic administration of 0.625 mg/kg lorcaserin significantly reduced alcohol intake up to 6h every day after the injection and there was no sign of diminished efficacy of the drug during 10-day treatment. To determine the effects of lorcaserin on sucrose intake, rats were put on a two-bottle choice of water vs a solution of 7% sucrose. The high dose of lorcaserin (1.25 mg/kg, s.c.) reduced sucrose intake only for up to 2 h. When tested for locomotor activity, lorcaserin injected 20 min before testing significantly reduced locomotor activity at all doses. However, when it was injected 5.5h before the start of the 1-h session, neither dose had a significant effect on locomotor activity. These results show the efficacy of lorcaserin in reducing alcohol intake without a significant effect on water intake and locomotion suggesting the involvement of 5-HT2c receptors in alcohol seeking behavior. Further research is warranted to determine the possible efficacy of lorcaserin or similar drugs as treatments for the treatment of alcoholism.

Authors
Rezvani, AH; Cauley, MC; Levin, ED
MLA Citation
Rezvani, AH, Cauley, MC, and Levin, ED. "Lorcaserin, a selective 5-HT(2C) receptor agonist, decreases alcohol intake in female alcohol preferring rats." Pharmacology, biochemistry, and behavior 125 (October 2014): 8-14.
PMID
25109272
Source
epmc
Published In
Pharmacology Biochemistry and Behavior
Volume
125
Publish Date
2014
Start Page
8
End Page
14
DOI
10.1016/j.pbb.2014.07.017

LONG-TERM BEHAVIORAL EFFECTS OF EMBRYONIC ETHANOL EXPOSURE IN ZEBRAFISH

Authors
Zhang, C; Bailey, JM; Oliveri, AN; Frazier, J; Delarosa, A; Crosby, E; Janardhan, S; Mackinnon, S; Levin, ED; Cole, GJ
MLA Citation
Zhang, C, Bailey, JM, Oliveri, AN, Frazier, J, Delarosa, A, Crosby, E, Janardhan, S, Mackinnon, S, Levin, ED, and Cole, GJ. "LONG-TERM BEHAVIORAL EFFECTS OF EMBRYONIC ETHANOL EXPOSURE IN ZEBRAFISH." June 2014.
Source
wos-lite
Published In
Alcoholism: Clinical and Experimental Research
Volume
38
Publish Date
2014
Start Page
176A
End Page
176A

Differential effects of non-nicotine tobacco constituent compounds on nicotine self-administration in rats.

Tobacco smoking has been shown to be quite addictive in people. However, nicotine itself is a weak reinforcer compared to other commonly abused drugs, leading speculation that other factors contribute to the high prevalence of tobacco addiction in the human population. In addition to nicotine, there are over 5000 chemical compounds that have been identified in tobacco smoke, and more work is needed to ascertain their potential contributions to tobacco's highly addictive properties, or as potential candidates for smoking cessation treatment. In this study, we examined seven non-nicotine tobacco constituent compounds (anabasine, anatabine, nornicotine, myosmine, harmane, norharmane, and tyramine) for their effects on nicotine self-administration behavior in rats. Young adult female Sprague-Dawley rats were allowed to self-administer nicotine (0.03 mg/kg/50 μl infusion) under a fixed ratio-1 schedule of reinforcement. Each self-administration session lasted 45 min. Doses of each tobacco constituent compound were administered subcutaneously 10 min prior to the start of each session in a repeated measures, counterbalanced order two times. Anabasine displayed a biphasic dose-effect function. Pretreatment with 0.02 mg/kg anabasine resulted in a 25% increase in nicotine self-administration, while 2.0mg/kg of anabasine reduced nicotine infusions per session by over 50%. Pretreatment with 2.0mg/kg anatabine also significantly reduced nicotine self-administration by nearly half. These results suggest that some non-nicotine tobacco constituents may enhance or reduce nicotine's reinforcing properties. Also, depending upon the appropriate dose, some of these compounds may also serve as potential smoking cessation agents.

Authors
Hall, BJ; Wells, C; Allenby, C; Lin, MY; Hao, I; Marshall, L; Rose, JE; Levin, ED
MLA Citation
Hall, BJ, Wells, C, Allenby, C, Lin, MY, Hao, I, Marshall, L, Rose, JE, and Levin, ED. "Differential effects of non-nicotine tobacco constituent compounds on nicotine self-administration in rats." Pharmacology, biochemistry, and behavior 120 (May 2014): 103-108.
PMID
24560911
Source
epmc
Published In
Pharmacology Biochemistry and Behavior
Volume
120
Publish Date
2014
Start Page
103
End Page
108
DOI
10.1016/j.pbb.2014.02.011

Effects of tobacco smoke on PC12 cell neurodifferentiation are distinct from those of nicotine or benzo[a]pyrene.

Although nicotine accounts for a great deal of the neurodevelopmental damage associated with maternal smoking or second-hand exposure, tobacco smoke contains thousands of potentially neurotoxic compounds. We used PC12 cells, a standard in vitro model of neurodifferentiation, to compare tobacco smoke extract (TSE) to nicotine, matching TSE exposure (with its inherent nicotine content) to parallel concentrations of nicotine, or to benzo[a]pyrene, a tobacco combustion product. TSE promoted the transition from cell replication to differentiation, resulting in fewer, but larger cells with greater neurite extension. TSE also biased differentiation into the dopaminergic versus the cholinergic phenotype, evidenced by an increase in tyrosine hydroxylase activity but not choline acetyltransferase. Nicotine likewise promoted differentiation at the expense of cell numbers, but its effect on growth and neurite extension was smaller than that of TSE; furthermore, nicotine did not promote the dopaminergic phenotype. Benzo[a]pyrene had effects opposite to those of TSE, retarding neurodifferentiation, which resulted in higher cell numbers, smaller cells, reduced neurite information, and impaired emergence of both dopaminergic and cholinergic phenotypes. Our studies show that the complex mixture of compounds in tobacco smoke exerts direct effects on neural cell replication and differentiation that resemble those of nicotine in some ways but not others, and most importantly, that are greater in magnitude than can be accounted for from just the nicotine content of TSE. Thus, fetal tobacco smoke exposure, including lower levels associated with second-hand smoke, could be more injurious than would be anticipated from measured levels of nicotine or its metabolites.

Authors
Slotkin, TA; Card, J; Stadler, A; Levin, ED; Seidler, FJ
MLA Citation
Slotkin, TA, Card, J, Stadler, A, Levin, ED, and Seidler, FJ. "Effects of tobacco smoke on PC12 cell neurodifferentiation are distinct from those of nicotine or benzo[a]pyrene." Neurotoxicology and teratology 43 (May 2014): 19-24.
PMID
24642111
Source
epmc
Published In
Neurotoxicology and Teratology
Volume
43
Publish Date
2014
Start Page
19
End Page
24
DOI
10.1016/j.ntt.2014.03.002

Sex-selective interaction of prenatal nicotine with neonatal chlorpyrifos on novel object recognition in rats

Authors
Cauley, M; Burke, D; Hall, BJ; Seidler, FJ; Slotkin, TA; Levin, ED
MLA Citation
Cauley, M, Burke, D, Hall, BJ, Seidler, FJ, Slotkin, TA, and Levin, ED. "Sex-selective interaction of prenatal nicotine with neonatal chlorpyrifos on novel object recognition in rats." May 2014.
Source
crossref
Published In
Neurotoxicology and Teratology
Volume
43
Publish Date
2014
Start Page
88
End Page
89
DOI
10.1016/j.ntt.2014.04.043

Nicotinic attention-deficit/hyperactivity disorder treatment.

Authors
Levin, ED
MLA Citation
Levin, ED. "Nicotinic attention-deficit/hyperactivity disorder treatment." Biol Psychiatry 75.3 (February 1, 2014): 174-.
PMID
24370349
Source
pubmed
Published In
Biological Psychiatry
Volume
75
Issue
3
Publish Date
2014
Start Page
174
DOI
10.1016/j.biopsych.2013.11.024

Meclizine enhancement of sensorimotor gating in healthy male subjects with high startle responses and low prepulse inhibition

Histamine H 1 receptor systems have been shown in animal studies to have important roles in the reversal of sensorimotor gating deficits, as measured by prepulse inhibition (PPI). H 1-antagonist treatment attenuates the PPI impairments caused by either blockade of NMDA glutamate receptors or facilitation of dopamine transmission. The current experiment brought the investigation of H 1 effects on sensorimotor gating to human studies. The effects of the histamine H 1 antagonist meclizine on the startle response and PPI were investigated in healthy male subjects with high baseline startle responses and low PPI levels. Meclizine was administered to participants (n=24) using a within-subjects design with each participant receiving 0, 12.5, and 25 mg of meclizine in a counterbalanced order. Startle response, PPI, heart rate response, galvanic skin response, and changes in self-report ratings of alertness levels and affective states (arousal and valence) were assessed. When compared with the control (placebo) condition, the two doses of meclizine analyzed (12.5 and 25 mg) produced significant increases in PPI without affecting the magnitude of the startle response or other physiological variables. Meclizine also caused a significant increase in overall self-reported arousal levels, which was not correlated with the observed increase in PPI. These results are in agreement with previous reports in the animal literature and suggest that H 1 antagonists may have beneficial effects in the treatment of subjects with compromised sensorimotor gating and enhanced motor responses to sensory stimuli. © 2014 American College of Neuropsychopharmacology.

Authors
Larrauri, JA; Kelley, LD; Jenkins, MR; Westman, EC; Schmajuk, NA; Rosenthal, MZ; Levin, ED
MLA Citation
Larrauri, JA, Kelley, LD, Jenkins, MR, Westman, EC, Schmajuk, NA, Rosenthal, MZ, and Levin, ED. "Meclizine enhancement of sensorimotor gating in healthy male subjects with high startle responses and low prepulse inhibition." Neuropsychopharmacology 39.3 (February 1, 2014): 651-659.
Source
scopus
Published In
Neuropsychopharmacology (Nature)
Volume
39
Issue
3
Publish Date
2014
Start Page
651
End Page
659
DOI
10.1038/npp.2013.248

Meclizine enhancement of sensorimotor gating in healthy male subjects with high startle responses and low prepulse inhibition.

Histamine H1 receptor systems have been shown in animal studies to have important roles in the reversal of sensorimotor gating deficits, as measured by prepulse inhibition (PPI). H1-antagonist treatment attenuates the PPI impairments caused by either blockade of NMDA glutamate receptors or facilitation of dopamine transmission. The current experiment brought the investigation of H1 effects on sensorimotor gating to human studies. The effects of the histamine H1 antagonist meclizine on the startle response and PPI were investigated in healthy male subjects with high baseline startle responses and low PPI levels. Meclizine was administered to participants (n=24) using a within-subjects design with each participant receiving 0, 12.5, and 25 mg of meclizine in a counterbalanced order. Startle response, PPI, heart rate response, galvanic skin response, and changes in self-report ratings of alertness levels and affective states (arousal and valence) were assessed. When compared with the control (placebo) condition, the two doses of meclizine analyzed (12.5 and 25 mg) produced significant increases in PPI without affecting the magnitude of the startle response or other physiological variables. Meclizine also caused a significant increase in overall self-reported arousal levels, which was not correlated with the observed increase in PPI. These results are in agreement with previous reports in the animal literature and suggest that H1 antagonists may have beneficial effects in the treatment of subjects with compromised sensorimotor gating and enhanced motor responses to sensory stimuli.

Authors
Larrauri, JA; Kelley, LD; Jenkins, MR; Westman, EC; Schmajuk, NA; Rosenthal, MZ; Levin, ED
MLA Citation
Larrauri, JA, Kelley, LD, Jenkins, MR, Westman, EC, Schmajuk, NA, Rosenthal, MZ, and Levin, ED. "Meclizine enhancement of sensorimotor gating in healthy male subjects with high startle responses and low prepulse inhibition." Neuropsychopharmacology 39.3 (February 2014): 651-659.
PMID
24045586
Source
pubmed
Published In
Neuropsychopharmacology
Volume
39
Issue
3
Publish Date
2014
Start Page
651
End Page
659
DOI
10.1038/npp.2013.248

Prenatal dexamethasone augments the neurobehavioral teratology of chlorpyrifos: significance for maternal stress and preterm labor.

Glucocorticoids are the consensus treatment given in preterm labor and are also elevated by maternal stress; organophosphate exposures are virtually ubiquitous, so human developmental coexposures to these two agents are common. This study explores how prenatal dexamethasone exposure modifies the neurobehavioral teratology of chlorpyrifos, one of the most widely used organophosphates. We administered dexamethasone to pregnant rats on gestational days 17-19 at a standard therapeutic dose (0.2 mg/kg); offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1 mg/kg) that produces barely-detectable (<10%) inhibition of brain cholinesterase activity. Dexamethasone did not alter brain chlorpyrifos concentrations, nor did either agent alone or in combination affect brain thyroxine levels. Assessments were carried out from adolescence through adulthood encompassing T-maze alternation, Figure 8 maze (locomotor activity, habituation), novelty-suppressed feeding and novel object recognition tests. For behaviors where chlorpyrifos or dexamethasone individually had small effects, the dual exposure produced larger, significant effects that reflected additivity (locomotor activity, novelty-suppressed feeding, novel object recognition). Where the individual effects were in opposite directions or were restricted to only one agent, we found enhancement of chlorpyrifos' effects by prenatal dexamethasone (habituation). Finally, for behaviors where controls displayed a normal sex difference in performance, the combined treatment either eliminated or reversed the difference (locomotor activity, novel object recognition). Combined exposure to dexamethasone and chlorpyrifos results in a worsened neurobehavioral outcome, providing a proof-of-principle that prenatal glucocorticoids can create a subpopulation with enhanced vulnerability to environmental toxicants.

Authors
Levin, ED; Cauley, M; Johnson, JE; Cooper, EM; Stapleton, HM; Ferguson, PL; Seidler, FJ; Slotkin, TA
MLA Citation
Levin, ED, Cauley, M, Johnson, JE, Cooper, EM, Stapleton, HM, Ferguson, PL, Seidler, FJ, and Slotkin, TA. "Prenatal dexamethasone augments the neurobehavioral teratology of chlorpyrifos: significance for maternal stress and preterm labor." Neurotoxicol Teratol 41 (January 2014): 35-42.
PMID
24177596
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
41
Publish Date
2014
Start Page
35
End Page
42
DOI
10.1016/j.ntt.2013.10.004

Effects of tobacco smoke constituents, anabasine and anatabine, on memory and attention in female rats

© The Author(s) 2014.Nicotine has been well characterized to improve memory and attention. Nicotine is the primary, but not only neuroactive compound in tobacco. O tobacco constituents such as anabasine and anatabine also have agonist actions on nicotinic receptors. The current study investigated the effect anabasine and anatabine on memory and attention. Adult female Sprague-Dawley rats were trained on a win-shift spatial working and reference me task in the 16-arm radial maze or a visual signal detection operant task to test attention. Acute dose-effect functions of anabasine and anata over two orders of magnitude were evaluated for both tasks. In the radial-arm maze memory test, anabasine but not anatabine significantly red the memory impairment caused by the NMDA antagonist dizocilpine (MK-801). In the signal detection attentional task, anatabine but not anaba significantly attenuated the attentional impairment caused by dizocilpine. These studies show that non-nicotine nicotinic agonists in tobacco, sim to nicotine, can significantly improve memory and attentional function. Both anabasine and anatabine produced cognitive improvement, but t effectiveness differed with regard to memory and attention. Follow-up studies with anabasine and anatabine are called for to determine their effi as therapeutics for memory and attentional dysfunction.

Authors
Levin, ED; Hao, I; Burke, DA; Cauley, M; Hall, BJ; Rezvani, AH
MLA Citation
Levin, ED, Hao, I, Burke, DA, Cauley, M, Hall, BJ, and Rezvani, AH. "Effects of tobacco smoke constituents, anabasine and anatabine, on memory and attention in female rats." Journal of Psychopharmacology 28.10 (2014): 915-922.
Source
scival
Published In
Journal of Psychopharmacology
Volume
28
Issue
10
Publish Date
2014
Start Page
915
End Page
922
DOI
10.1177/0269881114543721

Design, synthesis and discovery of picomolar selective α4β2 nicotinic acetylcholine receptor ligands.

Developing novel and selective compounds that desensitize α4β2 nicotinic acetylcholine receptors (nAChRs) could provide new effective treatments for nicotine addiction, as well as other disorders. Here we report a new class of nAChR ligands that display high selectivity and picomolar binding affinity for α4β2 nicotinic receptors. The novel compounds have Ki values in the range of 0.031-0.26 nM and properties that should make them good candidates as drugs acting in the CNS. The selected lead compound 1 (VMY-2-95) binds with high affinity and potently desensitizes α4β2 nAChRs. At a dose of 3 mg/kg, compound 1 significantly reduced rat nicotine self-administration. The overall results support further characterizations of compound 1 and its analogues in preclinical models of nicotine addiction and perhaps other disorders involving nAChRs.

Authors
Yenugonda, VM; Xiao, Y; Levin, ED; Rezvani, AH; Tran, T; Al-Muhtasib, N; Sahibzada, N; Xie, T; Wells, C; Slade, S; Johnson, JE; Dakshanamurthy, S; Kong, H-S; Tomita, Y; Liu, Y; Paige, M; Kellar, KJ; Brown, ML
MLA Citation
Yenugonda, VM, Xiao, Y, Levin, ED, Rezvani, AH, Tran, T, Al-Muhtasib, N, Sahibzada, N, Xie, T, Wells, C, Slade, S, Johnson, JE, Dakshanamurthy, S, Kong, H-S, Tomita, Y, Liu, Y, Paige, M, Kellar, KJ, and Brown, ML. "Design, synthesis and discovery of picomolar selective α4β2 nicotinic acetylcholine receptor ligands." J Med Chem 56.21 (November 14, 2013): 8404-8421.
PMID
24047231
Source
pubmed
Published In
Journal of Medicinal Chemistry
Volume
56
Issue
21
Publish Date
2013
Start Page
8404
End Page
8421
DOI
10.1021/jm4008455

Role of insular cortex D₁ and D₂ dopamine receptors in nicotine self-administration in rats.

The insular cortex has been associated with the processing of rewarding stimuli and with the neural bases of drug addiction. Ischemic damage to the insula has been associated with decreased desire to smoke cigarettes. Which component of insular function is involved in the neural basis of cigarette smoking is not clear. Dopamine systems are crucial for the reinforcing value of addictive drugs. The DA projection from the ventral tegmental area to the nucleus accumbens (NAc) has been shown to be a vital pathway for the primary reinforcement caused by taking a variety of abused drugs. In the current set of studies, the roles of D₁ and D₂ receptors in the insular cortex in the self-administration of nicotine by rats were assessed. Adult female Sprague-Dawley rats were fitted with jugular catheters and given access to self-administer nicotine. Bilateral local infusion cannulae were implanted into the agranular insular cortex to locally administer D₁ and D₂ antagonists (SCH-23390 and haloperidol). Acute local infusions of the D₁ antagonist SCH-23390 into the insula (1-2 μg/side) significantly decreased nicotine self-administration by more than 50%. Repeated infusions of SCH-23390 into the agranular insula caused continuing decreases in nicotine self-administration without signs of tolerance. In contrast, local infusions of the D₂ antagonist haloperidol 0.5-2 μg/side did not have any discernable effect on nicotine self-administration. These studies show the importance of DA D₁ systems in the insula for nicotine reward.

Authors
Kutlu, MG; Burke, D; Slade, S; Hall, BJ; Rose, JE; Levin, ED
MLA Citation
Kutlu, MG, Burke, D, Slade, S, Hall, BJ, Rose, JE, and Levin, ED. "Role of insular cortex D₁ and D₂ dopamine receptors in nicotine self-administration in rats." Behav Brain Res 256 (November 1, 2013): 273-278.
PMID
23948214
Source
pubmed
Published In
Behavioural Brain Research
Volume
256
Publish Date
2013
Start Page
273
End Page
278
DOI
10.1016/j.bbr.2013.08.005

Nicotinic alpha 4 beta 2 antagonist treatment attenuates impairments in radial-arm maze repeated acquisition caused by dizocilpine in rats

Authors
Burke, D; Levin, ED
MLA Citation
Burke, D, and Levin, ED. "Nicotinic alpha 4 beta 2 antagonist treatment attenuates impairments in radial-arm maze repeated acquisition caused by dizocilpine in rats." October 15, 2013.
Source
wos-lite
Published In
Biochemical Pharmacology
Volume
86
Issue
8
Publish Date
2013
Start Page
1231
End Page
1231
DOI
10.1016/j.bcp.2013.08.047

Complex relationships of nicotinic receptor actions and cognitive functions.

Nicotine has been shown in a variety of studies to improve cognitive function including learning, memory and attention. Nicotine both stimulates and desensitizes nicotinic receptors, thus acting both as an agonist and a net antagonist. The relative roles of these two actions for nicotine-induced cognitive improvement have not yet been fully determined. We and others have found that acute nicotinic antagonist treatment can improve learning and attention. Nicotine acts on a variety of nicotinic receptor subtypes. The relative role and interactions of neuronal nicotinic receptor subtypes for cognition also needs to be better characterized. Nicotine acts on nicotinic receptors in a wide variety of brain areas. The role of some of these areas such as the hippocampus has been relatively well studied but other areas like the thalamus, which has the densest nicotinic receptor concentration are still only partially characterized. In a series of studies we characterized nicotinic receptor actions, anatomic localization and circuit interactions, which are critical to nicotine effects on the cognitive functions of learning, memory and attention. The relative role of increases and decreases in nicotinic receptor activation by nicotine were determined in regionally specific studies of the hippocampus, the amygdala, the frontal cortex and the mediodorsal thalamic nucleus with local infusions of antagonists of nicotinic receptor subtypes (α7 and α4β2). The understanding of the functional neural bases of cognitive function is fundamental to the more effective development of nicotinic drugs for treating cognitive dysfunction.

Authors
Levin, ED
MLA Citation
Levin, ED. "Complex relationships of nicotinic receptor actions and cognitive functions." Biochem Pharmacol 86.8 (October 15, 2013): 1145-1152. (Review)
PMID
23928190
Source
pubmed
Published In
Biochemical Pharmacology
Volume
86
Issue
8
Publish Date
2013
Start Page
1145
End Page
1152
DOI
10.1016/j.bcp.2013.07.021

Effects of the sazetidine-a family of compounds on the body temperature in wildtype, nicotinic receptor β2-/- and α7-/- mice.

Nicotine elicits hypothermic responses in rodents. This effect appears to be related to nicotinic receptor desensitization because sazetidine-A, an α4β2 nicotinic receptor desensitizing agent, produces marked hypothermia and potentiates nicotine-induced hypothermia in mice. To determine the specificity of sazetidine-A induced hypothermia to β2 subunit-containing nicotinic receptors, we tested its efficacy in β2 knockout (β2(-/-)) mice. These effects were compared with wildtype (WT) and α7 knockout (α7(-/-)) mice. Confirming our earlier results, sazetidine-A elicited a pronounced and long-lasting hypothermia in WT mice. In comparison, sazetidine-A induced a much attenuated and shorter hypothermic response in β2(-/-) mice. This indicates that the greater proportion of sazetidine-A induced hypothermia is mediated via actions on β2-containing nicotinic receptors, while a smaller component of hypothermia induced by sazetidine-A is mediated by non-β2 receptors. Similar to WT mice, α7(-/-) mice showed the full extent of the sazetidine-A effect, suggesting that the hypothermia produced by sazetidine-A did not depend on actions on α7 nicotinic receptor subtype. Three other novel nicotinic receptor desensitizing agents derived from sazetidine-A, triazetidine-O, VMY-2-95 and YL-1-127 also produced hypothermia in WT and α7(-/-) mice. Furthermore, unlike sazetidine-A, triazetidine-O and YL-1-127 did not show any hint of a hypothermic effect in β2(-/-) mice. VMY-2-95 like sazetidine-A did show a residual hypothermic effect in the β2(-/-) mice. These studies show that the hypothermic effects of sazetidine-A and the related compound VMY-2-95 are mainly mediated by nicotinic receptors containing β2 subunit, but that a small component of the effect is apparently mediated by non-β2 containing receptors.

Authors
Levin, ED; Sexton, HG; Gordon, K; Gordon, CJ; Xiao, Y; Kellar, KJ; Yenugonda, VM; Liu, Y; White, MP; Paige, M; Brown, ML; Rezvani, AH
MLA Citation
Levin, ED, Sexton, HG, Gordon, K, Gordon, CJ, Xiao, Y, Kellar, KJ, Yenugonda, VM, Liu, Y, White, MP, Paige, M, Brown, ML, and Rezvani, AH. "Effects of the sazetidine-a family of compounds on the body temperature in wildtype, nicotinic receptor β2-/- and α7-/- mice." Eur J Pharmacol 718.1-3 (October 15, 2013): 167-172.
PMID
24036108
Source
pubmed
Published In
European Journal of Pharmacology
Volume
718
Issue
1-3
Publish Date
2013
Start Page
167
End Page
172
DOI
10.1016/j.ejphar.2013.08.037

Effects of the sazetidine-a family of compounds on the body temperature in wildtype, nicotinic receptor β2-/- and α7-/- mice

Nicotine elicits hypothermic responses in rodents. This effect appears to be related to nicotinic receptor desensitization because sazetidine-A, an α4β2 nicotinic receptor desensitizing agent, produces marked hypothermia and potentiates nicotine-induced hypothermia in mice. To determine the specificity of sazetidine-A induced hypothermia to β2 subunit-containing nicotinic receptors, we tested its efficacy in β2 knockout (β2-/-) mice. These effects were compared with wildtype (WT) and α7 knockout (α7-/-) mice. Confirming our earlier results, sazetidine-A elicited a pronounced and long-lasting hypothermia in WT mice. In comparison, sazetidine-A induced a much attenuated and shorter hypothermic response in β2-/- mice. This indicates that the greater proportion of sazetidine-A induced hypothermia is mediated via actions on β2-containing nicotinic receptors, while a smaller component of hypothermia induced by sazetidine-A is mediated by non-β2 receptors. Similar to WT mice, α7-/- mice showed the full extent of the sazetidine-A effect, suggesting that the hypothermia produced by sazetidine-A did not depend on actions on α7 nicotinic receptor subtype. Three other novel nicotinic receptor desensitizing agents derived from sazetidine-A, triazetidine-O, VMY-2-95 and YL-1-127 also produced hypothermia in WT and α7-/- mice. Furthermore, unlike sazetidine-A, triazetidine-O and YL-1-127 did not show any hint of a hypothermic effect in β2 -/- mice. VMY-2-95 like sazetidine-A did show a residual hypothermic effect in the β2-/- mice. These studies show that the hypothermic effects of sazetidine-A and the related compound VMY-2-95 are mainly mediated by nicotinic receptors containing β2 subunit, but that a small component of the effect is apparently mediated by non-β2 containing receptors. © 2013 Elsevier B.V.

Authors
Levin, ED; Sexton, HG; Gordon, K; Gordon, CJ; Xiao, Y; Kellar, KJ; Yenugonda, VM; Liu, Y; White, MP; Paige, M; Brown, ML; Rezvani, AH
MLA Citation
Levin, ED, Sexton, HG, Gordon, K, Gordon, CJ, Xiao, Y, Kellar, KJ, Yenugonda, VM, Liu, Y, White, MP, Paige, M, Brown, ML, and Rezvani, AH. "Effects of the sazetidine-a family of compounds on the body temperature in wildtype, nicotinic receptor β2-/- and α7-/- mice." European Journal of Pharmacology 718.1-3 (September 27, 2013): 167-172.
Source
scopus
Published In
European Journal of Pharmacology
Volume
718
Issue
1-3
Publish Date
2013
Start Page
167
End Page
172
DOI
10.1016/j.ejphar.2013.08.037

DESENSITIZATION OF A4 beta 2 NICOTINIC RECEPTORS ATTENUATES ALCOHOL INTAKE AND PREFERENCE IN ALCOHOL PREFERRING P RATS

Authors
Rezvani, AH; Xiao, Y; Brown, ML; Paige, MA; Yenugonda, VM; Kellar, KJ; Levin, ED
MLA Citation
Rezvani, AH, Xiao, Y, Brown, ML, Paige, MA, Yenugonda, VM, Kellar, KJ, and Levin, ED. "DESENSITIZATION OF A4 beta 2 NICOTINIC RECEPTORS ATTENUATES ALCOHOL INTAKE AND PREFERENCE IN ALCOHOL PREFERRING P RATS." June 2013.
Source
wos-lite
Published In
Alcoholism: Clinical and Experimental Research
Volume
37
Publish Date
2013
Start Page
247A
End Page
247A

Chemistry and pharmacological studies of 3-alkoxy-2,5-disubstituted-pyridinyl compounds as novel selective α4β2 nicotinic acetylcholine receptor ligands that reduce alcohol intake in rats.

Neuronal acetylcholine receptors mediate the addictive effects of nicotine and may also be involved in alcohol addiction. Varenicline, an approved smoking cessation medication, showed clear efficacy in reducing alcohol consumption in heavy-drinking smokers. More recently, sazetidine-A, which selectively desensitizes α4β2 nicotinic receptors, was shown to significantly reduce alcohol intake in a rat model. To develop novel therapeutics for treating alcohol use disorder, we designed and synthesized novel sazetidine-A analogues containing a methyl group at the 2-position of the pyridine ring. In vitro pharmacological studies revealed that some of the novel compounds showed overall pharmacological property profiles similar to that of sazetidine-A but exhibited reduced agonist activity across all nicotinic receptor subtypes tested. In rat studies, compound (S)-9 significantly reduced alcohol uptake. More importantly, preliminary results from studies in a ferret model indicate that these novel nAChR ligands have an improved adverse side-effect profile in comparison with that of varenicline.

Authors
Liu, Y; Richardson, J; Tran, T; Al-Muhtasib, N; Xie, T; Yenugonda, VM; Sexton, HG; Rezvani, AH; Levin, ED; Sahibzada, N; Kellar, KJ; Brown, ML; Xiao, Y; Paige, M
MLA Citation
Liu, Y, Richardson, J, Tran, T, Al-Muhtasib, N, Xie, T, Yenugonda, VM, Sexton, HG, Rezvani, AH, Levin, ED, Sahibzada, N, Kellar, KJ, Brown, ML, Xiao, Y, and Paige, M. "Chemistry and pharmacological studies of 3-alkoxy-2,5-disubstituted-pyridinyl compounds as novel selective α4β2 nicotinic acetylcholine receptor ligands that reduce alcohol intake in rats." J Med Chem 56.7 (April 11, 2013): 3000-3011.
PMID
23540678
Source
pubmed
Published In
Journal of Medicinal Chemistry
Volume
56
Issue
7
Publish Date
2013
Start Page
3000
End Page
3011
DOI
10.1021/jm4000374

Effects of chronic sazetidine-A, a selective α4β2 neuronal nicotinic acetylcholine receptors desensitizing agent on pharmacologically-induced impaired attention in rats.

RATIONALE: Nicotine and nicotinic agonists have been shown to improve attentional function. Nicotinic receptors are easily desensitized, and all nicotinic agonists are also desensitizing agents. Although both receptor activation and desensitization are components of the mechanism that mediates the overall effects of nicotinic agonists, it is not clear how each of the two opposed actions contributes to attentional improvements. Sazetidine-A has high binding affinity at α4β2 nicotinic receptors and causes a relatively brief activation followed by a long-lasting desensitization of the receptors. Acute administration of sazetidine-A has been shown to significantly improve attention by reversing impairments caused by the muscarinic cholinergic antagonist scopolamine and the NMDA glutamate antagonist dizocilpine. METHODS: In the current study, we tested the effects of chronic subcutaneous infusion of sazetidine-A (0, 2, or 6 mg/kg/day) on attention in Sprague-Dawley rats. Furthermore, we investigated the effects of chronic sazetidine-A treatment on attentional impairment induced by an acute administration of 0.02 mg/kg scopolamine. RESULTS: During the first week period, the 6-mg/kg/day sazetidine-A dose significantly reversed the attentional impairment induced by scopolamine. During weeks 3 and 4, the scopolamine-induced impairment was no longer seen, but sazetidine-A (6 mg/kg/day) significantly improved attentional performance on its own. Chronic sazetidine-A also reduced response latency and response omissions. CONCLUSIONS: This study demonstrated that similar to its acute effects, chronic infusions of sazetidine-A improve attentional performance. The results indicate that the desensitization of α4β2 nicotinic receptors with some activation of these receptors may play an important role in improving effects of sazetidine-A on attention.

Authors
Rezvani, AH; Cauley, M; Xiao, Y; Kellar, KJ; Levin, ED
MLA Citation
Rezvani, AH, Cauley, M, Xiao, Y, Kellar, KJ, and Levin, ED. "Effects of chronic sazetidine-A, a selective α4β2 neuronal nicotinic acetylcholine receptors desensitizing agent on pharmacologically-induced impaired attention in rats." Psychopharmacology (Berl) 226.1 (March 2013): 35-43.
PMID
23100170
Source
pubmed
Published In
Psychopharmacology
Volume
226
Issue
1
Publish Date
2013
Start Page
35
End Page
43
DOI
10.1007/s00213-012-2895-6

Zebrafish model systems for developmental neurobehavioral toxicology.

Zebrafish offer many advantages that complement classic mammalian models for the study of normal development as well as for the teratogenic effects of exposure to hazardous compounds. The clear chorion and embryo of the zebrafish allow for continuous visualization of the anatomical changes associated with development, which, along with short maturation times and the capability of complex behavior, makes this model particularly useful for measuring changes to the developing nervous system. Moreover, the rich array of developmental, behavioral, and molecular benefits offered by the zebrafish have contributed to an increasing demand for the use of zebrafish in behavioral teratology. Essential for this endeavor has been the development of a battery of tests to evaluate a spectrum of behavior in zebrafish. Measures of sensorimotor plasticity, emotional function, cognition and social interaction have been used to characterize the persisting adverse effects of developmental exposure to a variety of chemicals including therapeutic drugs, drugs of abuse and environmental toxicants. In this review, we present and discuss such tests and data from a range of developmental neurobehavioral toxicology studies using zebrafish as a model. Zebrafish provide a key intermediate model between high throughput in vitro screens and the classic mammalian models as they have the accessibility of in vitro models and the complex functional capabilities of mammalian models.

Authors
Bailey, J; Oliveri, A; Levin, ED
MLA Citation
Bailey, J, Oliveri, A, and Levin, ED. "Zebrafish model systems for developmental neurobehavioral toxicology." Birth Defects Res C Embryo Today 99.1 (March 2013): 14-23. (Review)
PMID
23723169
Source
pubmed
Published In
Birth Defects Research Part C: Embryo Today: Reviews
Volume
99
Issue
1
Publish Date
2013
Start Page
14
End Page
23
DOI
10.1002/bdrc.21027

Improvement of attentional function with antagonism of nicotinic receptors in female rats.

Nicotinic agonists have been shown in a variety of studies to improve cognitive function. Since nicotinic receptors are easily desensitized by agonists, it is not completely clear to what degree receptor desensitization or receptor activation are responsible for nicotinic agonist-induced cognitive improvement. In the current study, the effect of the neuronal nicotinic cholinergic α4β2 receptor antagonist dihydro-β-erythroidine (DHβE) and the α7 nicotinic receptor antagonist methyllycaconitine (MLA) on attentional function was determined. Adult female Sprague-Dawley rats were trained on the visual signal detection task. They were required to discriminate whether or not a light signal occurred on a trial and respond with a lever press on one side after a signal and the opposite side after the absence of a signal in order to receive a food pellet reinforcer. Acute administration of the α4β2 antagonist DHβE improved attentional function either alone or in reversing the attentional impairment caused by the NMDA glutamate antagonist dizocilpine (MK-801). Acute administration of MLA also significantly attenuated the dizocilpine-induced attentional impairment. In previous research we have shown that the α4β2 nicotinic desensitizing agent and partial agonist sazetidine-A also was effective in reversing dizocilpine-induced attentional impairments on the signal detection task and that low doses of the general nicotinic antagonist mecamylamine improved learning and memory. The current studies indicate that blockade of nicotinic receptors can effectively attenuate attentional impairments. Development of drugs that provide a net decrease in nicotinic receptor activity either through antagonism or desensitization could be worth exploring for beneficial effects for treating cognitive impairments.

Authors
Levin, ED; Cauley, M; Rezvani, AH
MLA Citation
Levin, ED, Cauley, M, and Rezvani, AH. "Improvement of attentional function with antagonism of nicotinic receptors in female rats." Eur J Pharmacol 702.1-3 (February 28, 2013): 269-274.
PMID
23399762
Source
pubmed
Published In
European Journal of Pharmacology
Volume
702
Issue
1-3
Publish Date
2013
Start Page
269
End Page
274
DOI
10.1016/j.ejphar.2013.01.056

Branched-chain amino acids alter neurobehavioral function in rats.

Recently, we have described a strong association of branched-chain amino acids (BCAA) and aromatic amino acids (AAA) with obesity and insulin resistance. In the current study, we have investigated the potential impact of BCAA on behavioral functions. We demonstrate that supplementation of either a high-sucrose or a high-fat diet with BCAA induces anxiety-like behavior in rats compared with control groups fed on unsupplemented diets. These behavioral changes are associated with a significant decrease in the concentration of tryptophan (Trp) in brain tissues and a consequent decrease in serotonin but no difference in indices of serotonin synaptic function. The anxiety-like behaviors and decreased levels of Trp in the brain of BCAA-fed rats were reversed by supplementation of Trp in the drinking water but not by administration of fluoxetine, a selective serotonin reuptake inhibitor, suggesting that the behavioral changes are independent of the serotonergic pathway of Trp metabolism. Instead, BCAA supplementation lowers the brain levels of another Trp-derived metabolite, kynurenic acid, and these levels are normalized by Trp supplementation. We conclude that supplementation of high-energy diets with BCAA causes neurobehavioral impairment. Since BCAA are elevated spontaneously in human obesity, our studies suggest a potential mechanism for explaining the strong association of obesity and mood disorders.

Authors
Coppola, A; Wenner, BR; Ilkayeva, O; Stevens, RD; Maggioni, M; Slotkin, TA; Levin, ED; Newgard, CB
MLA Citation
Coppola, A, Wenner, BR, Ilkayeva, O, Stevens, RD, Maggioni, M, Slotkin, TA, Levin, ED, and Newgard, CB. "Branched-chain amino acids alter neurobehavioral function in rats." Am J Physiol Endocrinol Metab 304.4 (February 15, 2013): E405-E413.
PMID
23249694
Source
pubmed
Published In
American journal of physiology. Endocrinology and metabolism
Volume
304
Issue
4
Publish Date
2013
Start Page
E405
End Page
E413
DOI
10.1152/ajpendo.00373.2012

Evaluation of the association between maternal smoking, childhood obesity, and metabolic disorders: a national toxicology program workshop review.

BACKGROUND: An emerging literature suggests that environmental chemicals may play a role in the development of childhood obesity and metabolic disorders, especially when exposure occurs early in life. OBJECTIVE: Here we assess the association between these health outcomes and exposure to maternal smoking during pregnancy as part of a broader effort to develop a research agenda to better understand the role of environmental chemicals as potential risk factors for obesity and metabolic disorders. METHODS: PubMed was searched up to 8 March 2012 for epidemiological and experimental animal studies related to maternal smoking or nicotine exposure during pregnancy and childhood obesity or metabolic disorders at any age. A total of 101 studies-83 in humans and 18 in animals-were identified as the primary literature. DISCUSSION: Current epidemiological data support a positive association between maternal smoking and increased risk of obesity or overweight in offspring. The data strongly suggest a causal relation, although the possibility that the association is attributable to unmeasured residual confounding cannot be completely ruled out. This conclusion is supported by findings from laboratory animals exposed to nicotine during development. The existing literature on human exposures does not support an association between maternal smoking during pregnancy and type 1 diabetes in offspring. Too few human studies have assessed outcomes related to type 2 diabetes or metabolic syndrome to reach conclusions based on patterns of findings. There may be a number of mechanistic pathways important for the development of aberrant metabolic outcomes following perinatal exposure to cigarette smoke, which remain largely unexplored. CONCLUSIONS: From a toxicological perspective, the linkages between maternal smoking during pregnancy and childhood overweight/obesity provide proof-of-concept of how early-life exposure to an environmental toxicant can be a risk factor for childhood obesity.

Authors
Behl, M; Rao, D; Aagaard, K; Davidson, TL; Levin, ED; Slotkin, TA; Srinivasan, S; Wallinga, D; White, MF; Walker, VR; Thayer, KA; Holloway, AC
MLA Citation
Behl, M, Rao, D, Aagaard, K, Davidson, TL, Levin, ED, Slotkin, TA, Srinivasan, S, Wallinga, D, White, MF, Walker, VR, Thayer, KA, and Holloway, AC. "Evaluation of the association between maternal smoking, childhood obesity, and metabolic disorders: a national toxicology program workshop review." Environ Health Perspect 121.2 (February 2013): 170-180. (Review)
PMID
23232494
Source
pubmed
Published In
Environmental health perspectives
Volume
121
Issue
2
Publish Date
2013
Start Page
170
End Page
180
DOI
10.1289/ehp.1205404

Long-term effects of chronic intermittent ethanol exposure in adolescent and adult rats: radial-arm maze performance and operant food reinforced responding.

Adolescence is not only a critical period of late-stage neurological development in humans, but is also a period in which ethanol consumption is often at its highest. Given the prevalence of ethanol use during this vulnerable developmental period we assessed the long-term effects of chronic intermittent ethanol (CIE) exposure during adolescence, compared to adulthood, on performance in the radial-arm maze (RAM) and operant food-reinforced responding in male rats.Male Sprague Dawley rats were exposed to CIE (or saline) and then allowed to recover. Animals were then trained in either the RAM task or an operant task using fixed- and progressive- ratio schedules. After baseline testing was completed all animals received an acute ethanol challenge while blood ethanol levels (BECs) were monitored in a subset of animals. CIE exposure during adolescence, but not adulthood decreased the amount of time that animals spent in the open portions of the RAM arms (reminiscent of deficits in risk-reward integration) and rendered animals more susceptible to the acute effects of an ethanol challenge on working memory tasks. The operant food reinforced task showed that these effects were not due to altered food motivation or to differential sensitivity to the nonspecific performance-disrupting effects of ethanol. However, CIE pre-treated animals had lower BEC levels than controls during the acute ethanol challenges indicating persistent pharmacokinetic tolerance to ethanol after the CIE treatment. There was little evidence of enduring effects of CIE alone on traditional measures of spatial and working memory.These effects indicate that adolescence is a time of selective vulnerability to the long-term effects of repeated ethanol exposure on neurobehavioral function and acute ethanol sensitivity. The positive and negative findings reported here help to further define the nature and extent of the impairments observed after adolescent CIE and provide direction for future research.

Authors
Risher, M-L; Fleming, RL; Boutros, N; Semenova, S; Wilson, WA; Levin, ED; Markou, A; Swartzwelder, HS; Acheson, SK
MLA Citation
Risher, M-L, Fleming, RL, Boutros, N, Semenova, S, Wilson, WA, Levin, ED, Markou, A, Swartzwelder, HS, and Acheson, SK. "Long-term effects of chronic intermittent ethanol exposure in adolescent and adult rats: radial-arm maze performance and operant food reinforced responding." PloS one 8.5 (January 2013): e62940-.
PMID
23675442
Source
epmc
Published In
PloS one
Volume
8
Issue
5
Publish Date
2013
Start Page
e62940
DOI
10.1371/journal.pone.0062940

Complex relationships of nicotinic receptor actions and cognitive functions

Nicotine has been shown in a variety of studies to improve cognitive function including learning, memory and attention. Nicotine both stimulates and desensitizes nicotinic receptors, thus acting both as an agonist and a net antagonist. The relative roles of these two actions for nicotine-induced cognitive improvement have not yet been fully determined. We and others have found that acute nicotinic antagonist treatment can improve learning and attention. Nicotine acts on a variety of nicotinic receptor subtypes. The relative role and interactions of neuronal nicotinic receptor subtypes for cognition also needs to be better characterized. Nicotine acts on nicotinic receptors in a wide variety of brain areas. The role of some of these areas such as the hippocampus has been relatively well studied but other areas like the thalamus, which has the densest nicotinic receptor concentration are still only partially characterized. In a series of studies we characterized nicotinic receptor actions, anatomic localization and circuit interactions, which are critical to nicotine effects on the cognitive functions of learning, memory and attention. The relative role of increases and decreases in nicotinic receptor activation by nicotine were determined in regionally specific studies of the hippocampus, the amygdala, the frontal cortex and the mediodorsal thalamic nucleus with local infusions of antagonists of nicotinic receptor subtypes (α7 and α4β2). The understanding of the functional neural bases of cognitive function is fundamental to the more effective development of nicotinic drugs for treating cognitive dysfunction. © 2013 Elsevier Inc. All rights reserved.

Authors
Levin, ED
MLA Citation
Levin, ED. "Complex relationships of nicotinic receptor actions and cognitive functions." Biochemical Pharmacology 86.8 (2013): 1145-1152.
Source
scival
Published In
Biochemical Pharmacology
Volume
86
Issue
8
Publish Date
2013
Start Page
1145
End Page
1152
DOI
10.1016/j.bcp.2013.07.021

Effects of caffeine on alcohol consumption and nicotine self-administration in rats

Background: Caffeine, alcohol, and nicotine are 3 of the most widespread self-administered psychoactive substances, which are known to be extensively co-administered. However, little is known about the degree to which they may mutually potentiate each other's consumption. Methods: In the current set of studies, we examined in rats the effect of caffeine administration on alcohol drinking and intravenous (i.v.) self-administration of nicotine. In male alcohol-preferring (P) rats, caffeine (5, 10, and 20 mg/kg) or the saline vehicle was administered acutely either by subcutaneous (S.C.) injection or orally (PO) by gavage. In a chronic study, the effect of PO caffeine (5 and 20 mg/kg) on alcohol intake over a 10-day period was tested. In another experiment, the effect of acute PO administration of caffeine (20 mg/kg) or saline on saccharin intake (0.2% solution) was determined in P rats. Effects of 20 mg/kg caffeine on motor activity were also determined in P rats. Finally, the effects of acute PO caffeine administration on nicotine self-administration in Sprague-Dawley rats were also determined. Results: Both routes of administration of caffeine, S.C. and PO, caused a significant dose-related decrease in alcohol intake and preference during free access to alcohol and after 4-day deprivation of alcohol. However, the low dose of 5 mg/kg caffeine increased alcohol intake. Acute PO caffeine also reduced saccharin intake. Acute systemic administration of 20 mg/kg caffeine did not exert a significant effect on motor activity. In Sprague-Dawley rats trained to self-administer i.v. nicotine, acute PO administration of caffeine significantly increased self-administration of nicotine in a dose-related manner. Conclusions: These results suggest that adenosine receptor systems may play a role in both alcohol and nicotine intake and deserve further study regarding these addictions. © 2013 by the Research Society on Alcoholism.

Authors
Rezvani, AH; Sexton, HG; Johnson, J; Wells, C; Gordon, K; Levin, ED
MLA Citation
Rezvani, AH, Sexton, HG, Johnson, J, Wells, C, Gordon, K, and Levin, ED. "Effects of caffeine on alcohol consumption and nicotine self-administration in rats." Alcoholism: Clinical and Experimental Research (2013).
PMID
23895206
Source
scival
Published In
Alcoholism: Clinical and Experimental Research
Publish Date
2013
DOI
10.1111/acer.12127

Effects of chronic sazetidine-A, a selective α4β2 neuronal nicotinic acetylcholine receptors desensitizing agent on pharmacologically- induced impaired attention in rats

Rationale: Nicotine and nicotinic agonists have been shown to improve attentional function. Nicotinic receptors are easily desensitized, and all nicotinic agonists are also desensitizing agents. Although both receptor activation and desensitization are components of the mechanism that mediates the overall effects of nicotinic agonists, it is not clear how each of the two opposed actions contributes to attentional improvements. Sazetidine-A has high binding affinity at α4β2 nicotinic receptors and causes a relatively brief activation followed by a long-lasting desensitization of the receptors. Acute administration of sazetidine-A has been shown to significantly improve attention by reversing impairments caused by the muscarinic cholinergic antagonist scopolamine and the NMDA glutamate antagonist dizocilpine. Methods: In the current study, we tested the effects of chronic subcutaneous infusion of sazetidine-A (0, 2, or 6 mg/kg/day) on attention in Sprague-Dawley rats. Furthermore, we investigated the effects of chronic sazetidine-A treatment on attentional impairment induced by an acute administration of 0.02 mg/kg scopolamine. Results: During the first week period, the 6-mg/kg/day sazetidine-A dose significantly reversed the attentional impairment induced by scopolamine. During weeks 3 and 4, the scopolamine-induced impairment was no longer seen, but sazetidine-A (6 mg/kg/day) significantly improved attentional performance on its own. Chronic sazetidine-A also reduced response latency and response omissions. Conclusions: This study demonstrated that similar to its acute effects, chronic infusions of sazetidine-A improve attentional performance. The results indicate that the desensitization of α4β2 nicotinic receptors with some activation of these receptors may play an important role in improving effects of sazetidine-A on attention. © 2012 Springer-Verlag Berlin Heidelberg.

Authors
Rezvani, AH; Cauley, M; Xiao, Y; Kellar, KJ; Levin, ED
MLA Citation
Rezvani, AH, Cauley, M, Xiao, Y, Kellar, KJ, and Levin, ED. "Effects of chronic sazetidine-A, a selective α4β2 neuronal nicotinic acetylcholine receptors desensitizing agent on pharmacologically- induced impaired attention in rats." Psychopharmacology 226.1 (2013): 35-43.
Source
scival
Published In
Psychopharmacology
Volume
226
Issue
1
Publish Date
2013
Start Page
35
End Page
43
DOI
10.1007/s00213-012-2895-6

Effects of caffeine on alcohol consumption and nicotine self-administration in rats

Background: Caffeine, alcohol, and nicotine are 3 of the most widespread self-administered psychoactive substances, which are known to be extensively co-administered. However, little is known about the degree to which they may mutually potentiate each other's consumption. Methods: In the current set of studies, we examined in rats the effect of caffeine administration on alcohol drinking and intravenous (i.v.) self-administration of nicotine. In male alcohol-preferring (P) rats, caffeine (5, 10, and 20 mg/kg) or the saline vehicle was administered acutely either by subcutaneous (S.C.) injection or orally (PO) by gavage. In a chronic study, the effect of PO caffeine (5 and 20 mg/kg) on alcohol intake over a 10-day period was tested. In another experiment, the effect of acute PO administration of caffeine (20 mg/kg) or saline on saccharin intake (0.2% solution) was determined in P rats. Effects of 20 mg/kg caffeine on motor activity were also determined in P rats. Finally, the effects of acute PO caffeine administration on nicotine self-administration in Sprague-Dawley rats were also determined. Results: Both routes of administration of caffeine, S.C. and PO, caused a significant dose-related decrease in alcohol intake and preference during free access to alcohol and after 4-day deprivation of alcohol. However, the low dose of 5 mg/kg caffeine increased alcohol intake. Acute PO caffeine also reduced saccharin intake. Acute systemic administration of 20 mg/kg caffeine did not exert a significant effect on motor activity. In Sprague-Dawley rats trained to self-administer i.v. nicotine, acute PO administration of caffeine significantly increased self-administration of nicotine in a dose-related manner. Conclusions: These results suggest that adenosine receptor systems may play a role in both alcohol and nicotine intake and deserve further study regarding these addictions. © 2013 by the Research Society on Alcoholism.

Authors
Rezvani, AH; Sexton, HG; Johnson, J; Wells, C; Gordon, K; Levin, ED
MLA Citation
Rezvani, AH, Sexton, HG, Johnson, J, Wells, C, Gordon, K, and Levin, ED. "Effects of caffeine on alcohol consumption and nicotine self-administration in rats." Alcoholism: Clinical and Experimental Research 37.9 (2013): 1609-1617.
Source
scival
Published In
Alcoholism: Clinical and Experimental Research
Volume
37
Issue
9
Publish Date
2013
Start Page
1609
End Page
1617
DOI
10.1111/acer.12127

Chronic sazetidine-A at behaviorally active doses does not increase nicotinic cholinergic receptors in rodent brain.

Chronic nicotine administration increases α4β2 neuronal nicotinic acetylcholine receptor (nAChR) density in brain. This up-regulation probably contributes to the development and/or maintenance of nicotine dependence. nAChR up-regulation is believed to be triggered at the ligand binding site, so it is not surprising that other nicotinic ligands also up-regulate nAChRs in the brain. These other ligands include varenicline, which is currently used for smoking cessation therapy. Sazetidine-A (saz-A) is a newer nicotinic ligand that binds with high affinity and selectivity at α4β2* nAChRs. In behavioral studies, saz-A decreases nicotine self-administration and increases performance on tasks of attention. We report here that, unlike nicotine and varenicline, chronic administration of saz-A at behaviorally active and even higher doses does not up-regulate nAChRs in rodent brains. We used a newly developed method involving radioligand binding to measure the concentrations and nAChR occupancy of saz-A, nicotine, and varenicline in brains from chronically treated rats. Our results indicate that saz-A reached concentrations in the brain that were ∼150 times its affinity for α4β2* nAChRs and occupied at least 75% of nAChRs. Thus, chronic administration of saz-A did not up-regulate nAChRs despite it reaching brain concentrations that are known to bind and desensitize virtually all α4β2* nAChRs in brain. These findings reinforce a model of nicotine addiction based on desensitization of up-regulated nAChRs and introduce a potential new strategy for smoking cessation therapy in which drugs such as saz-A can promote smoking cessation without maintaining nAChR up-regulation, thereby potentially increasing the rate of long-term abstinence from nicotine.

Authors
Hussmann, GP; Turner, JR; Lomazzo, E; Venkatesh, R; Cousins, V; Xiao, Y; Yasuda, RP; Wolfe, BB; Perry, DC; Rezvani, AH; Levin, ED; Blendy, JA; Kellar, KJ
MLA Citation
Hussmann, GP, Turner, JR, Lomazzo, E, Venkatesh, R, Cousins, V, Xiao, Y, Yasuda, RP, Wolfe, BB, Perry, DC, Rezvani, AH, Levin, ED, Blendy, JA, and Kellar, KJ. "Chronic sazetidine-A at behaviorally active doses does not increase nicotinic cholinergic receptors in rodent brain." J Pharmacol Exp Ther 343.2 (November 2012): 441-450.
PMID
22899752
Source
pubmed
Published In
The Journal of pharmacology and experimental therapeutics
Volume
343
Issue
2
Publish Date
2012
Start Page
441
End Page
450
DOI
10.1124/jpet.112.198085

Effects of ethanol, Δ(9)-tetrahydrocannabinol, or their combination on object recognition memory and object preference in adolescent and adult male rats.

Recent advances have been made in our understanding of the deleterious effects of both ethanol and THC on adolescent behavior and brain development. However, very little is known about the combined effects of EtOH+THC during adolescence, a time in which these drugs are often used together. The purpose of this experiment was to: (1) determine whether EtOH and/or THC induced greater working memory impairment in adolescent than adult male rats using the novel object recognition (NOR) task and (2) determine whether the EtOH+THC combination would produce a more potent additive effect in adolescents than adults when compared to these drugs alone. NOR was performed with a 24h delay under each of the four drug conditions: vehicle; 1.5g/kg ethanol; 1.0mg/kg THC; and 1.5g/kg EtOH+1.0mg/kg THC, at 72h intervals. The results show that there was an age effect on working memory in NOR after the EtOH+THC challenge. Specifically, adolescent animals showed a preference for the familiar object whereas adults showed no preference for the novel or familiar object, the latter being characteristic of a classic working memory deficit. These effects were not dependent on changes in exploration across session, global activity across drug condition, or total object exploration. These novel findings clearly indicate that further understanding of this age-drug interaction is crucial to elucidating the influence that adolescent EtOH+THC use may have on repeated drug use and abuse later in life.

Authors
Swartzwelder, NA; Risher, ML; Abdelwahab, SH; D'Abo, A; Rezvani, AH; Levin, ED; Wilson, WA; Swartzwelder, HS; Acheson, SK
MLA Citation
Swartzwelder, NA, Risher, ML, Abdelwahab, SH, D'Abo, A, Rezvani, AH, Levin, ED, Wilson, WA, Swartzwelder, HS, and Acheson, SK. "Effects of ethanol, Δ(9)-tetrahydrocannabinol, or their combination on object recognition memory and object preference in adolescent and adult male rats." Neuroscience letters 527.1 (October 2012): 11-15.
PMID
22959891
Source
epmc
Published In
Neuroscience Letters
Volume
527
Issue
1
Publish Date
2012
Start Page
11
End Page
15
DOI
10.1016/j.neulet.2012.08.037

Effects of AZD3480, a neuronal nicotinic acetylcholine receptor agonist, and donepezil on dizocilpine-induced attentional impairment in rats.

BACKGROUND AND RATIONALE: Nicotinic acetylcholine systems play major roles in cognitive function. Nicotine and a variety of nicotinic agonists improve attention, and nicotinic antagonist exposure impairs it. This study was conducted to investigate the effect of a novel nicotinic receptor agonist at α4β2 nicotinic receptors (AZD3480) on attention and reversal of pharmacologically induced attentional impairment produced by the NMDA glutamate antagonist dizocilpine (MK-801). METHODS: Adult female Sprague-Dawley rats were trained to perform an operant visual signal detection task to a stable baseline of accuracy. The rats were then injected subcutaneously following a repeated measures, counter-balanced design with saline, AZD3480 (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations 30 min before the test. The effect of donepezil on the same pharmacologically induced attentional impairment was also tested. A separate group of rats was injected with donepezil (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations, and their attention were assessed. Saline was the vehicle control. RESULTS: Dizocilpine caused a significant (p < 0.0005) impairment in percent correct performance. This attentional impairment was significantly (p < 0.0005) reversed by 0.01 and 0.1 mg/kg of AZD3480. AZD3480 by itself did not alter the already high baseline control performance. Donepezil (0.01-1.0 mg/kg) also significantly (p < 0.005) attenuated the dizocilpine-induced attentional impairment. CONCLUSIONS: AZD3480, similar to donepezil, showed significant efficacy for counteracting the attentional impairment caused by the NMDA glutamate antagonist dizocilpine. Low doses of AZD3480 may provide therapeutic benefit for reversing attentional impairment in patients suffering from cognitive impairment due to glutamatergic dysregulation and likely other attentional disorders.

Authors
Rezvani, AH; Cauley, MC; Johnson, EC; Gatto, GJ; Levin, ED
MLA Citation
Rezvani, AH, Cauley, MC, Johnson, EC, Gatto, GJ, and Levin, ED. "Effects of AZD3480, a neuronal nicotinic acetylcholine receptor agonist, and donepezil on dizocilpine-induced attentional impairment in rats." Psychopharmacology (Berl) 223.3 (October 2012): 251-258.
PMID
22526540
Source
pubmed
Published In
Psychopharmacology
Volume
223
Issue
3
Publish Date
2012
Start Page
251
End Page
258
DOI
10.1007/s00213-012-2712-2

Design, synthesis, and characterization of picomolar selective a4b2 nicotinic acetylcholine receptor inhibitors

Authors
Yenugonda, VM; Xiao, Y; Levin, ED; Rezvani, AH; Tran, TT; Al-Muhtasib, N; Wells, C; Slade, S; Johnson, JE; Kong, H-S; Dakshanamurthy, S; Tomita, Y; Liu, Y; Paige, MA; Kellar, KJ; Brown, ML
MLA Citation
Yenugonda, VM, Xiao, Y, Levin, ED, Rezvani, AH, Tran, TT, Al-Muhtasib, N, Wells, C, Slade, S, Johnson, JE, Kong, H-S, Dakshanamurthy, S, Tomita, Y, Liu, Y, Paige, MA, Kellar, KJ, and Brown, ML. "Design, synthesis, and characterization of picomolar selective a4b2 nicotinic acetylcholine receptor inhibitors." August 19, 2012.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
244
Publish Date
2012

Novel medication targets for the treatment of alcoholism: preclinical studies.

Alcoholism is a complex heterogeneous disease and a number of neurotransmitter and neuromodulator systems have been implicated in its manifestation. Consequently, it is unlikely that existing medications such as disulfiram (Antabuse®), naltrexone (ReVia®), acamprosate (Campral®)) can be efficacious in every individual. Thus, the development of novel therapeutic agents with greater selectivity and less unwanted effects for the treatment of this disease is one of the major objectives of alcohol research. This review summarizes the findings of five novel compounds with different neuronal targets for treating alcoholism. These compounds include sazetidine-A, which selectively desensitizes α4β2 nicotinic receptors; carisbamate, a novel anti-epileptic agent; JNJ5234801, a novel anxiolytic agent; GS-455534, a highly selective inhibitor of mitochondrial aldehyde dehydrogenase; and JNJ-39220675, a selective histamine H3 antagonist. Inbred alcohol-preferring rats (iP), Fawn-Hooded (FH) rats, and P rats were used to evaluate the compounds. Naltrexone was used as a positive control in some experiments. All five compounds reduced alcohol consumption and preference. The mechanisms thought to underlie these effects suggest that, in addition to dopaminergic and opioidergic systems, other neuronal systems such as sodium channels (carisbamate), mitochondrial aldehyde dehydrogenase (GS-455534), 5-HT2 receptors (JNJ-5234801), histamine H3 receptors (JNJ-39220675), and α4β2 nicotinic receptors (sazetidine-A) can be involved in alcohol drinking. Further work is necessary to confirm the exact mechanisms of action of each drug and to determine any viable targets for putative treatment of alcohol-use disorders. The article presents some promising patents on novel medication targets for the treatment of alcoholism.

Authors
Rezvani, AH; Lawrence, AJ; Arolfo, MP; Levin, ED; Overstreet, DH
MLA Citation
Rezvani, AH, Lawrence, AJ, Arolfo, MP, Levin, ED, and Overstreet, DH. "Novel medication targets for the treatment of alcoholism: preclinical studies." Recent Pat CNS Drug Discov 7.2 (August 2012): 151-162. (Review)
PMID
22574676
Source
pubmed
Published In
Recent Patents on CNS Drug Discovery
Volume
7
Issue
2
Publish Date
2012
Start Page
151
End Page
162

Assessing the effects of chronic sazetidine-A delivery on nicotine self-administration in both male and female rats.

RATIONALE: Sazetidine-A is a selective α4β2 nicotinic receptor desensitizing agent and partial agonist. It has been shown in previous studies to significantly reduce nicotine self-administration in rats after acute or repeated injections. However, the effects of continuous chronic infusions of sazetidine-A on maintenance of nicotine self-administration and relapse after abstinence have yet to be examined. OBJECTIVES: This study evaluated the efficacy of continuous sazetidine-A infusions (sc) over a period of 4 weeks to reduce nicotine self-administration in male and female Sprague-Dawley rats. METHODS: Sazetidine-A was administered via Alzet osmotic minipumps to young adult female and male rats at doses of 0, 2 or 6 mg/kg/day for 4 weeks. The effects of sazetidine-A on IV nicotine self-administration were examined in repeated 3-h sessions over the first 2 weeks of infusion followed by 1 week of forced abstinence from nicotine and 1 week of resumed nicotine access. RESULTS: The 6 mg/kg/day sazetidine-A dose significantly reduced overall nicotine self-administration compared with vehicle control across the sessions for both male (p < 0.001) and female (p < 0.05) rats. The lower 2 mg/kg/day sazetidine-A infusion dose was effective in reducing nicotine self-administration for male (p < 0.001), but not female rats. No attenuation in sazetidine-A effectiveness was seen over the course of the 4-week treatment. In the vehicle control group, male rats self-administered significantly (p < 0.001) more nicotine than females. CONCLUSIONS: The continuing effectiveness of sazetidine-A in reducing nicotine self-administration in both male and female rats supports its promise as a new treatment to help people successfully quit smoking.

Authors
Johnson, JE; Slade, S; Wells, C; Petro, A; Sexton, H; Rezvani, AH; Brown, ML; Paige, MA; McDowell, BE; Xiao, Y; Kellar, KJ; Levin, ED
MLA Citation
Johnson, JE, Slade, S, Wells, C, Petro, A, Sexton, H, Rezvani, AH, Brown, ML, Paige, MA, McDowell, BE, Xiao, Y, Kellar, KJ, and Levin, ED. "Assessing the effects of chronic sazetidine-A delivery on nicotine self-administration in both male and female rats." Psychopharmacology (Berl) 222.2 (July 2012): 269-276.
PMID
22297831
Source
pubmed
Published In
Psychopharmacology
Volume
222
Issue
2
Publish Date
2012
Start Page
269
End Page
276
DOI
10.1007/s00213-012-2642-z

Differential effects of the antidepressant mirtazapine on amphetamine- and dizocilpine-induced PPI deficits.

Prepulse inhibition (PPI) refers to the decrease in motor startle response to salient sensory stimuli (pulses) when they are closely preceded in time by another more modest sensory stimulus (prepulse). PPI deficits can be induced by stimulation of dopamine receptors (e.g., amphetamine or apomorphine) or blockade of NMDA glutamate receptors (e.g., dizocilpine or PCP). Previously we found that antagonists of α(2)-noradrenergic and H(1)-histaminergic receptors significantly attenuate PPI impairments caused by amphetamine or dizocilpine. In the current study we assessed the effects of the antidepressant mirtazapine, which has combined antagonist effects at α(2)-noradrenergic, H(1)-histaminergic and 5-HT serotonergic receptors, on amphetamine- and dizocilpine-induced PPI deficits. In Experiment 1, rats were tested for PPI of the startle response to a tactile air-puff stimulus after auditory prepulses of three different intensities. Drug treatments consisted of combinations of amphetamine (0 and 1mg/kg) and mirtazapine (0, 0.5, 1, 2, and 5mg/kg), with all rats receiving all drug doses and combinations with different counterbalanced orders. In Experiment 2, a different group of rats was tested with drug treatments consisting of combinations of dizocilpine (0 and 0.05 mg/kg) and mirtazapine (0, 0.5, 1, 2, and 5 mg/kg). In Experiment 1 amphetamine (1 mg/kg) significantly reduced PPI whereas mirtazapine caused the opposite effect, with the highest dose of mirtazapine (5 mg/kg) effectively reversing the amphetamine-induced PPI deficit. In Experiment 2 dizocilpine (0.05 mg/kg) significantly reduced PPI, but mirtazapine did not have a significant effect on the inhibition of the startle response. These results indicate that the potential beneficial effects of combined α-adrenergic, 5-HT, and H(1) receptor blockade in counteracting PPI deficits may be associated to cases of sensorimotor gating disorders mediated by dopamine, but not necessarily to NMDA glutamate-induced PPI impairments.

Authors
Larrauri, JA; Levin, ED
MLA Citation
Larrauri, JA, and Levin, ED. "Differential effects of the antidepressant mirtazapine on amphetamine- and dizocilpine-induced PPI deficits." Pharmacol Biochem Behav 102.1 (July 2012): 82-87.
PMID
22469866
Source
pubmed
Published In
Pharmacology, Biochemistry and Behavior
Volume
102
Issue
1
Publish Date
2012
Start Page
82
End Page
87
DOI
10.1016/j.pbb.2012.03.010

ASSESSMENT OF PREGNENOLONE EFFECTS ON ALCOHOL INTAKE IN MALE ALCOHOL PREFERRING RATS

Authors
Rezvani, AH; Sexton, HG; Levin, ED
MLA Citation
Rezvani, AH, Sexton, HG, and Levin, ED. "ASSESSMENT OF PREGNENOLONE EFFECTS ON ALCOHOL INTAKE IN MALE ALCOHOL PREFERRING RATS." June 2012.
PMID
25016089
Source
wos-lite
Published In
Alcoholism: Clinical and Experimental Research
Volume
36
Publish Date
2012
Start Page
101A
End Page
101A

Effects of sazetidine-A, a selective α4β2* nicotinic receptor desensitizing agent, on body temperature regulation in mice and rats.

Nicotine-induced hypothermia is well established, but the nicotinic receptor actions underlying this effect are not clear. Nicotine causes activation and desensitization at a variety of nicotinic receptor subtypes. Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a novel compound that potently and selectively desensitizes α4β2* nicotinic receptors. The main goal of this study was to investigate the effects of sazetidine-A, on core body temperature (Tc) in mice and rats. Sazetidine-A effects on Tc and the interactions of sazetidine-A with nicotine and selective nicotinic antagonists were investigated to determine the receptor actions underlying nicotine-induced hypothermia. Adult male mice were injected with different dose of nicotine (0.2, 0.4 and 0.8 mg/kg), sazetidine-A (0.3, 1, and 3mg/kg), a mixture of nicotine (0.4 or 0.8 mg/kg) and sazetidine-A (0.3 or 0.6 mg/kg) or saline and Tc was monitored telemetrically. In another set of experiments, the interaction between sazetidine-A and dihydro-β-erythroidine (DHβE), an α4β2* nicotinic receptors antagonist, and methyllycaconitine (MLA), an α7 antagonist, was investigated. Tc of mice was monitored following DHβE (1, 3 and 6 mg/kg), a combination of DHβE (3mg/kg) and sazetidine-A (0.6 mg/kg), MLA (1.5, 3 or 6 mg/kg) or combination of MLA (6 mg/kg) and sazetidine (0.6 mg/kg) or saline. The acute effect of sazetidine-A (1, 3, and 6 mg/kg) on rats Tc was also studied. Acute sazetidine-A caused a pronounced and long-lasting hypothermia in mice; Tc decreased to about 28°C at 100 min and recovered within 230 min. The hypothermic effect of sazetidine in rats was much less in magnitude (about 3°C) and shorter in duration compared with that in mice. Nicotine co-administration with low doses of sazetidine potentiated the magnitude and duration of hypothermia in mice. The α4β2* nicotinic receptors antagonist DHβE significantly prolonged sazetidine-A-induced hypothermia but did not increase its depth. The α7 antagonist MLA caused a modest degree of hypothermia with relatively short duration in mice. MLA failed to counteract the sazetidine-A-induced hypothermia. Overall, our results show that pharmacological modulation of α4β2* nicotinic receptors elicits changes in body temperature that may involve desensitization of these receptors.

Authors
Rezvani, AH; Timofeeva, O; Sexton, HG; DeCuir, D; Xiao, Y; Gordon, CJ; Kellar, KJ; Levin, ED
MLA Citation
Rezvani, AH, Timofeeva, O, Sexton, HG, DeCuir, D, Xiao, Y, Gordon, CJ, Kellar, KJ, and Levin, ED. "Effects of sazetidine-A, a selective α4β2* nicotinic receptor desensitizing agent, on body temperature regulation in mice and rats." Eur J Pharmacol 682.1-3 (May 5, 2012): 110-117.
PMID
22387853
Source
pubmed
Published In
European Journal of Pharmacology
Volume
682
Issue
1-3
Publish Date
2012
Start Page
110
End Page
117
DOI
10.1016/j.ejphar.2012.02.031

α7-Nicotinic receptors and cognition.

Nicotinic α7 receptors have been shown in a variety of studies with animal models to play important roles in diverse components of cognitive function, including learning, memory and attention. Mice with α7 receptor knockouts show impairments in memory. Selective α7 agonists significantly improve learning, memory and attention. α7 receptors in limbic structures such as the hippocampus and amygdala have been demonstrated to play critical roles in memory. Blockade of α7 receptors in these areas cause memory impairments. In the brains of people with schizophrenia α7 receptors are impaired. This may be related to pronounced cognitive impairments seen with schizophrenia. There has been a major effort to develop α7 nicotinic agonists for helping to reverse cognitive impairment. These receptors are a promising target for development of therapeutic treatments for a variety of diseases of cognitive impairment including Alzheimer's disease, attention deficit hyperactivity disorder (ADHD) and schizophrenia.

Authors
Levin, ED
MLA Citation
Levin, ED. "α7-Nicotinic receptors and cognition." Current drug targets 13.5 (May 2012): 602-606.
Source
epmc
Published In
Current Drug Targets
Volume
13
Issue
5
Publish Date
2012
Start Page
602
End Page
606
DOI
10.2174/138945012800398937

α7-Nicotinic receptors and cognition.

Nicotinic α7 receptors have been shown in a variety of studies with animal models to play important roles in diverse components of cognitive function, including learning, memory and attention. Mice with α7 receptor knockouts show impairments in memory. Selective α7 agonists significantly improve learning, memory and attention. α7 receptors in limbic structures such as the hippocampus and amygdala have been demonstrated to play critical roles in memory. Blockade of α7 receptors in these areas cause memory impairments. In the brains of people with schizophrenia α7 receptors are impaired. This may be related to pronounced cognitive impairments seen with schizophrenia. There has been a major effort to develop α7 nicotinic agonists for helping to reverse cognitive impairment. These receptors are a promising target for development of therapeutic treatments for a variety of diseases of cognitive impairment including Alzheimer's disease, attention deficit hyperactivity disorder (ADHD) and schizophrenia.

Authors
Levin, ED
MLA Citation
Levin, ED. "α7-Nicotinic receptors and cognition." Curr Drug Targets 13.5 (May 2012): 602-606. (Review)
PMID
22300026
Source
pubmed
Published In
Current Drug Targets
Volume
13
Issue
5
Publish Date
2012
Start Page
602
End Page
606

The α2-adrenergic antagonist idazoxan counteracts prepulse inhibition deficits caused by amphetamine or dizocilpine in rats

Rationale: Prepulse inhibition (PPI) is the reduction in startle response magnitude when intense stimuli are closely preceded by other weak stimuli. Animal models used to investigate sensorimotor gating deficits include both the stimulation of dopamine receptors (e.g., amphetamine or apomorphine) and the blockade of NMDA-glutamate receptors (e.g., dizocilpine or phencyclidine). Objectives: We assessed the effects of idazoxan (an α2- adrenergic antagonist) on amphetamine- and dizocilpine-induced PPI disruptions in adult female Sprague-Dawley rats. Methods: In experiment 1, rats were tested for PPI in a bimodal paradigm with an acoustic prepulse and a tactile startle stimulus. Interactions of amphetamine (1 mg/kg) and idazoxan (0.5, 1, and 2 mg/kg) were assessed, with all rats receiving all drug doses in a counterbalanced order. In experiment 2, dizocilpine (0.05 mg/kg) and idazoxan (0.5, 1, and 2 mg/kg) interactions were analyzed. Results: Amphetamine (1 mg/kg) caused a significant reduction in PPI. Both the 1- and 2-mg/kg doses of idazoxan significantly counteracted this effect. Dizocilpine (.05 mg/kg) effectively inhibited PPI, and the 2-mg/kg idazoxan dose significantly counteracted this impairment. Conclusions: These results suggest that the effectiveness of atypical antipsychotics such as clozapine in counteracting sensorimotor gating deficits reported in previous studies (e.g., Swerdlow and Geyer, Pharmacol Biochem Behav 44:741-744, 1993; Bakshi et al., J Pharmacol Exp Ther 271:787-794, 1994) may be related to their α2-antagonist effects, which may be a critical mechanism of the therapeutic effects of atypical antipsychotics in schizophrenia. © 2011 Springer-Verlag.

Authors
Larrauri, JA; Levin, ED
MLA Citation
Larrauri, JA, and Levin, ED. "The α2-adrenergic antagonist idazoxan counteracts prepulse inhibition deficits caused by amphetamine or dizocilpine in rats." Psychopharmacology 219.1 (January 1, 2012): 99-108.
Source
scopus
Published In
Psychopharmacology
Volume
219
Issue
1
Publish Date
2012
Start Page
99
End Page
108
DOI
10.1007/s00213-011-2377-2

The α₂-adrenergic antagonist idazoxan counteracts prepulse inhibition deficits caused by amphetamine or dizocilpine in rats.

RATIONALE: Prepulse inhibition (PPI) is the reduction in startle response magnitude when intense stimuli are closely preceded by other weak stimuli. Animal models used to investigate sensorimotor gating deficits include both the stimulation of dopamine receptors (e.g., amphetamine or apomorphine) and the blockade of NMDA-glutamate receptors (e.g., dizocilpine or phencyclidine). OBJECTIVES: We assessed the effects of idazoxan (an α(2)-adrenergic antagonist) on amphetamine- and dizocilpine-induced PPI disruptions in adult female Sprague-Dawley rats. METHODS: In experiment 1, rats were tested for PPI in a bimodal paradigm with an acoustic prepulse and a tactile startle stimulus. Interactions of amphetamine (1 mg/kg) and idazoxan (0.5, 1, and 2 mg/kg) were assessed, with all rats receiving all drug doses in a counterbalanced order. In experiment 2, dizocilpine (0.05 mg/kg) and idazoxan (0.5, 1, and 2 mg/kg) interactions were analyzed. RESULTS: Amphetamine (1 mg/kg) caused a significant reduction in PPI. Both the 1- and 2-mg/kg doses of idazoxan significantly counteracted this effect. Dizocilpine (.05 mg/kg) effectively inhibited PPI, and the 2-mg/kg idazoxan dose significantly counteracted this impairment. CONCLUSIONS: These results suggest that the effectiveness of atypical antipsychotics such as clozapine in counteracting sensorimotor gating deficits reported in previous studies (e.g., Swerdlow and Geyer, Pharmacol Biochem Behav 44:741-744, 1993; Bakshi et al., J Pharmacol Exp Ther 271:787-794, 1994) may be related to their α(2)-antagonist effects, which may be a critical mechanism of the therapeutic effects of atypical antipsychotics in schizophrenia.

Authors
Larrauri, JA; Levin, ED
MLA Citation
Larrauri, JA, and Levin, ED. "The α₂-adrenergic antagonist idazoxan counteracts prepulse inhibition deficits caused by amphetamine or dizocilpine in rats." Psychopharmacology (Berl) 219.1 (January 2012): 99-108.
PMID
21710169
Source
pubmed
Published In
Psychopharmacology
Volume
219
Issue
1
Publish Date
2012
Start Page
99
End Page
108
DOI
10.1007/s00213-011-2377-2

Effects of unexpected changes in visual scenes on the human acoustic startle response and prepulse inhibition.

Prepulse inhibition (PPI) refers to the process wherein startle responses to salient stimuli (e.g., startling sound pulses) are attenuated by the presentation of another stimulus (e.g., a brief pre-pulse) immediately before the startling stimulus. Accordingly, deficits in PPI reflect atypical sensorimotor gating that is linked to neurobehavioral systems underlying responsivity to emotionally evocative cues. Little is known about the effects of changes in visual contextual information in PPI among humans. In this study, the effects of introducing unexpected changes in the visual scenes presented on a computer monitor on the human auditory startle response and PPI were assessed in young adults. Based on our animal data showing that unexpected transitions from a dark to a light environment reduce the startle response and PPI in rats after the illumination transition, it was hypothesized that novel changes in visual scenes would produce similar effects in humans. Results show that PPI decreased when elements were added to or removed from visual scenes, and that this effect declined after repeated presentations of the modified scene, supporting the interpretation that the PPI reduction was due to novel information being processed. These findings are the first to demonstrate that novel visual stimuli can impair sensorimotor gating of auditory stimuli in humans.

Authors
Larrauri, JA; Rosenthal, MZ; Levin, ED; McClernon, FJ; Schmajuk, NA
MLA Citation
Larrauri, JA, Rosenthal, MZ, Levin, ED, McClernon, FJ, and Schmajuk, NA. "Effects of unexpected changes in visual scenes on the human acoustic startle response and prepulse inhibition." Behav Processes 89.1 (January 2012): 1-7.
PMID
22001728
Source
pubmed
Published In
Behavioural Processes
Volume
89
Issue
1
Publish Date
2012
Start Page
1
End Page
7
DOI
10.1016/j.beproc.2011.09.011

Brief embryonic strychnine exposure in zebrafish causes long-term adult behavioral impairment with indications of embryonic synaptic changes

Zebrafish provide a powerful model of the impacts of embryonic toxicant exposure on neural development that may result in long-term behavioral dysfunction. In this study, zebrafish embryos were treated with 1.5. mM strychnine for short embryonic time windows to induce transient changes in inhibitory neural signaling, and were subsequently raised in untreated water until adulthood. PCR analysis showed indications that strychnine exposure altered expression of some genes related to glycinergic, GABAergic and glutamatergic neuronal synapses during embryonic development. In adulthood, treated fish showed significant changes in swimming speed and tank diving behavior compared to controls. Taken together, these data show that a short embryonic exposure to a neurotoxicant can alter development of neural synapses and lead to changes in adult behavior. © 2012 Elsevier Inc.

Authors
Roy, NM; Arpie, B; Lugo, J; Linney, E; Levin, ED; Cerutti, D
MLA Citation
Roy, NM, Arpie, B, Lugo, J, Linney, E, Levin, ED, and Cerutti, D. "Brief embryonic strychnine exposure in zebrafish causes long-term adult behavioral impairment with indications of embryonic synaptic changes." Neurotoxicology and Teratology 34.6 (2012): 587-591.
PMID
23022260
Source
scival
Published In
Neurotoxicology and Teratology
Volume
34
Issue
6
Publish Date
2012
Start Page
587
End Page
591
DOI
10.1016/j.ntt.2012.08.001

Nicotine treatment of mild cognitive impairment: A 6-month double-blind pilot clinical trial

Objective: To preliminarily assess the safety and efficacy of transdermal nicotine therapy on cognitive performance and clinical status in subjects with mild cognitive impairment (MCI). Methods: Nonsmoking subjects with amnestic MCI were randomized to transdermal nicotine (15 mg per day or placebo) for 6 months. Primary outcome variables were attentional improvement assessed with Connors Continuous Performance Test (CPT), clinical improvement as measured by clinical global impression, and safety measures. Secondary measures included computerized cognitive testing and patient and observer ratings. Results: Of 74 subjects enrolled, 39 were randomized to nicotine and 35 to placebo. 67 subjects completed (34 nicotine, 33 placebo). The primary cognitive outcome measure (CPT) showed a significant nicotine-induced improvement. There was no statistically significant effect on clinician-rated global improvement. The secondary outcome measures showed significant nicotine-associated improvements in attention, memory, and psychomotor speed, and improvements were seen in patient/informant ratings of cognitive impairment. Safety and tolerability for transdermal nicotine were excellent. Conclusion: This study demonstrated that transdermal nicotine can be safely administered to nonsmoking subjects with MCI over 6 months with improvement in primary and secondary cognitive measures of attention, memory, and mental processing, but not in ratings of clinician-rated global impression. We conclude that this initial study provides evidence for nicotine-induced cognitive improvement in subjects with MCI; however, whether these effects are clinically important will require larger studies. Classification of evidence: This study provides Class I evidence that 6 months of transdermal nicotine (15 mg/day) improves cognitive test performance, but not clinical global impression of change, in nonsmoking subjects with amnestic MCI. Copyright © 2012 by AAN Enterprises, Inc.

Authors
Newhouse, P; Kellar, K; Aisen, P; White, H; Wesnes, K; Coderre, E; Pfaff, A; Wilkins, H; Howard, D; Levin, ED
MLA Citation
Newhouse, P, Kellar, K, Aisen, P, White, H, Wesnes, K, Coderre, E, Pfaff, A, Wilkins, H, Howard, D, and Levin, ED. "Nicotine treatment of mild cognitive impairment: A 6-month double-blind pilot clinical trial." Neurology 78.2 (2012): 91-101.
PMID
22232050
Source
scival
Published In
Neurology
Volume
78
Issue
2
Publish Date
2012
Start Page
91
End Page
101
DOI
10.1212/WNL.0b013e31823efcbb

Mouse models for studying genetic influences on factors determining smoking cessation success in humans

Humans differ in their ability to quit using addictive substances, including nicotine, the major psychoactive ingredient in tobacco. For tobacco smoking, a substantial body of evidence, largely derived from twin studies, indicates that approximately half of these individual differences in ability to quit are heritable genetic influences that likely overlap with those for other addictive substances. Both twin and molecular genetic studies support overlapping influences on nicotine addiction vulnerability and smoking cessation success, although there is little formal analysis of the twin data that support this important point. None of the current datasets provides clarity concerning which heritable factors might provide robust dimensions around which individuals differ in ability to quit smoking. One approach to this problem is to test mice with genetic variations in genes that contain human variants that alter quit success. This review considers which features of quit success should be included in a comprehensive approach to elucidate the genetics of quit success, and how those features may be modeled in mice. © 2012 New York Academy of Sciences.

Authors
Hall, FS; Markou, A; Levin, ED; Uhl, GR
MLA Citation
Hall, FS, Markou, A, Levin, ED, and Uhl, GR. "Mouse models for studying genetic influences on factors determining smoking cessation success in humans." Annals of the New York Academy of Sciences 1248.1 (2012): 39-70.
PMID
22304675
Source
scival
Published In
Annals of the New York Academy of Sciences
Volume
1248
Issue
1
Publish Date
2012
Start Page
39
End Page
70
DOI
10.1111/j.1749-6632.2011.06415.x

Threshold of adulthood for the onset of nicotine self-administration in male and female rats.

The great majority of tobacco addiction begins during adolescence. More heavily addicted smokers begin smoking earlier, but differentiating the neurobehavioral impact of nicotine self-administration during adolescence from self-selection bias (whereby people more prone to heavy addiction also begin earlier) cannot be ethically unconfounded in humans. The goals of this research were to determine the age threshold for the adult-like nicotine self-administration and determine sex differences. Male and female Sprague-Dawley rats were tested for nicotine self-administration starting at 4, 5, 6, 7, and 8 weeks of age in an operant FR1 schedule for IV nicotine (0.03 mg/kg/infusion) in 45-min sessions for 2 weeks, with 1 week of enforced abstinence and 1 week of resumed access. This study replicated our earlier work that nicotine self-administration was increased in adolescent vs. adult rats and that the effect was more pronounced in adolescent males, but the increased nicotine self-administration was more persistent in adolescent-onset females. The age threshold for adult-like behavior was 6-7 weeks of age. Adolescent-onset nicotine self-administration had persisting effects of eggaurated increases of nicotine self-administration when fixed-ratio requirements for self-administration were lowered. Female rats that had begun nicotine self-administration during adolescence showed exaggerated increases in nicotine self-administration after a switch back to FR1 from FR8, indicating a lessened control over their self-administration. Adolescent-onset nicotine self-administration was not found to potentiate cocaine self-administration. Adolescent-onset nicotine self-administration causes persistent increases in nicotine self-administration in female rats even after they reach adulthood and disrupts control over self-administration behavior.

Authors
Levin, ED; Slade, S; Wells, C; Cauley, M; Petro, A; Vendittelli, A; Johnson, M; Williams, P; Horton, K; Rezvani, AH
MLA Citation
Levin, ED, Slade, S, Wells, C, Cauley, M, Petro, A, Vendittelli, A, Johnson, M, Williams, P, Horton, K, and Rezvani, AH. "Threshold of adulthood for the onset of nicotine self-administration in male and female rats." Behav Brain Res 225.2 (December 1, 2011): 473-481.
PMID
21854810
Source
pubmed
Published In
Behavioural Brain Research
Volume
225
Issue
2
Publish Date
2011
Start Page
473
End Page
481
DOI
10.1016/j.bbr.2011.08.005

Glutamate and nicotinic receptor interactions in working memory: importance for the cognitive impairment of schizophrenia.

This article reaches across disciplines to correlate results in molecular, cellular, behavioral, and clinical research to develop a more complete picture of how working memory (WM) functions. It identifies a new idea that deserves further investigation. NMDA glutamate receptors (NMDAR) are critical for memory function. NMDAR inhibition effectively reproduces principal manifestations of schizophrenia (SP), such as WM impairment and GABAergic deficit (mainly reduction of glutamic acid decarboxylase 67 (GAD67) and parvalbumin (PV) content). Nicotine and selective α7 nicotinic acetylcholine receptor (nAChR) agonists reduce WM impairments in patients with SP and reverse WM deficits in animals treated with NMDAR antagonists. The mechanism of this effect is unknown. Importantly, WM recovery occurs even before restoration of NMDAR blockade-induced molecular alterations, including reduced GAD67 in interneurons. Our insight into the cognitive-enhancing effect of α7 nAChR agonists, particularly in the animal models of SP, combines reviews of recent findings on glutamate and nicotinic receptor expression in the neuronal circuits involved in WM, the properties of these receptors, their implication in WM regulation, generation of rhythmic neuronal activity, resulting in a proposed hypothesis for further investigations. We suggest that (1) cortical/hippocampal interneurons, particularly PV positive, play a crucial role in WM and that impairment of these cells in SP could be behind the WM deficit; (2) activation of α7 nAChRs could restore calcium signaling and intrinsic properties of these interneurons, and associated with these events, computational capacity, gamma rhythmic activity, and WM would also be restored.

Authors
Timofeeva, OA; Levin, ED
MLA Citation
Timofeeva, OA, and Levin, ED. "Glutamate and nicotinic receptor interactions in working memory: importance for the cognitive impairment of schizophrenia." Neuroscience 195 (November 10, 2011): 21-36. (Review)
PMID
21884762
Source
pubmed
Published In
Neuroscience
Volume
195
Publish Date
2011
Start Page
21
End Page
36
DOI
10.1016/j.neuroscience.2011.08.038

Differential acetylcholinesterase inhibition of chlorpyrifos, diazinon and parathion in larval zebrafish.

Zebrafish are increasingly used for developmental neurotoxicity testing because early embryonic events are easy to visualize, exposures are done without affecting the mother and the rapid development of zebrafish allows for high throughput testing. We used zebrafish to examine how exposures to three different organophosphorus pesticides (chlorpyrifos, diazinon and parathion) over the first five days of embryonic and larval development of zebrafish affected their survival, acetylcholinesterase (AChE) activity and behavior. We show that at non-lethal, equimolar concentrations, chlorpyrifos (CPF) is more effective at equimolar concentrations than diazinon (DZN) and parathion (PA) in producing AChE inhibition. As concentrations of DZN and PA are raised, lethality occurs before they can produce the degree of AChE inhibition observed with CPF at 300 nM. Because of its availability outside the mother at the time of fertilization, zebrafish provides a complementary model for studying the neurotoxicity of very early developmental exposures.

Authors
Yen, J; Donerly, S; Levin, ED; Linney, EA
MLA Citation
Yen, J, Donerly, S, Levin, ED, and Linney, EA. "Differential acetylcholinesterase inhibition of chlorpyrifos, diazinon and parathion in larval zebrafish." Neurotoxicol Teratol 33.6 (November 2011): 735-741.
PMID
22036888
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
33
Issue
6
Publish Date
2011
Start Page
735
End Page
741
DOI
10.1016/j.ntt.2011.10.004

Introduction to zebrafish: current discoveries and emerging technologies for neurobehavioral toxicology and teratology.

Authors
Levin, ED; Tanguay, RL
MLA Citation
Levin, ED, and Tanguay, RL. "Introduction to zebrafish: current discoveries and emerging technologies for neurobehavioral toxicology and teratology." Neurotoxicol Teratol 33.6 (November 2011): 607-.
PMID
22117689
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
33
Issue
6
Publish Date
2011
Start Page
607
DOI
10.1016/j.ntt.2011.10.005

Critical duration of exposure for developmental chlorpyrifos-induced neurobehavioral toxicity.

Developmental exposure of rats to the pesticide chlorpyrifos (CPF) causes persistent neurobehavioral impairment. In a parallel series of studies with zebrafish, we have also found persisting behavioral dysfunction after developmental CPF exposure. We have developed a battery of measures of zebrafish behavior, which are reliable and sensitive to toxicant-induced damage. This study determined the critical duration of developmental CPF exposure for causing persisting neurobehavioral effects. Tests of sensorimotor response (tap startle response and habituation), stress response (novel tank diving test) and learning (3-chamber tank spatial discrimination) were conducted with adult zebrafish after early developmental CPF exposure. The CPF exposure level was 100 ng/ml with durations of 0-1, 0-2, 0-3, 0-4 and 0-5 days after fertilization. Developmental CPF exposure had persisting behavioral effects in zebrafish tested as adults. In the tactile startle test, CPF exposed fish showed decreased habituation to startle and a trend toward increased overall startle response. In the novel tank exploration test, exposed fish showed decreased escape diving response and increased swimming activity. In the 3-chamber learning test, the 0-5 day CPF exposure group had a significantly lower learning rate. There was evidence for persisting declines in brain dopamine and norepinepherine levels after developmental CPF exposure. In all of the measures the clearest persistent effects were seen in fish exposed for the full duration of five days after fertilization. In a follow-up experiment there were some indications for persisting behavioral effects after exposure during only the later phase of this developmental window. This study demonstrated the selective long-term neurobehavioral alterations caused by exposure to CPF in zebrafish. The zebrafish model can facilitate the determination of the molecular mechanisms underlying long-term neurobehavioral impairment after developmental toxicant exposure.

Authors
Sledge, D; Yen, J; Morton, T; Dishaw, L; Petro, A; Donerly, S; Linney, E; Levin, ED
MLA Citation
Sledge, D, Yen, J, Morton, T, Dishaw, L, Petro, A, Donerly, S, Linney, E, and Levin, ED. "Critical duration of exposure for developmental chlorpyrifos-induced neurobehavioral toxicity." Neurotoxicol Teratol 33.6 (November 2011): 742-751.
PMID
21745564
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
33
Issue
6
Publish Date
2011
Start Page
742
End Page
751
DOI
10.1016/j.ntt.2011.06.005

Persistent behavioral impairment caused by embryonic methylphenidate exposure in zebrafish.

As more adults take the stimulant medication methylphenidate to treat attention deficit hyperactivity disorder (ADHD) residual type, the risk arises with regard to exposure during early development if people taking the medication become pregnant. We studied the neurobehavioral effects of methylphenidate in zebrafish. Zebrafish offer cellular reporter systems, continuous visual access and molecular interventions such as morpholinos to help determine critical mechanisms underlying neurobehavioral teratogenicity. Previously, we had seen that persisting neurobehavioral impairment in zebrafish with developmental chlorpyrifos exposure was associated with disturbed dopamine systems. Because methylphenidate is an indirect dopamine agonist, it was thought that it might also cause persistent behavioral impairment after developmental exposure. Zebrafish embryos were exposed to the ADHD stimulant medication methylphenidate 0-5 days post fertilization (12.5-50mg/l). They were tested for long-term behavioral effects as adults. Methylphenidate exposure (50mg/l) caused significant increases in dopamine, norepinepherine and serotonin on day 6 but not day 30 after fertilization. In the novel tank diving test of predatory avoidance developmental methylphenidate (50mg/l) caused a significant reduction in the normal diving response. In the three-chamber spatial learning task early developmental methylphenidate (50mg/l) caused a significant impairment in choice accuracy. These data show that early developmental exposure of zebrafish to methylphenidate causes a long-term impairment in neurobehavioral plasticity. The identification of these functional deficits in zebrafish enables further studies with this model to determine how molecular and cellular mechanisms are disturbed to arrive at this compromised state.

Authors
Levin, ED; Sledge, D; Roach, S; Petro, A; Donerly, S; Linney, E
MLA Citation
Levin, ED, Sledge, D, Roach, S, Petro, A, Donerly, S, and Linney, E. "Persistent behavioral impairment caused by embryonic methylphenidate exposure in zebrafish." Neurotoxicol Teratol 33.6 (November 2011): 668-673.
PMID
21741476
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
33
Issue
6
Publish Date
2011
Start Page
668
End Page
673
DOI
10.1016/j.ntt.2011.06.004

Attentional improvement in rats with the nicotinic agonist AZ12564698 (AZD3480)

Authors
Rezvani, AH; Cauley, M; Johnson, E; Levin, ED
MLA Citation
Rezvani, AH, Cauley, M, Johnson, E, and Levin, ED. "Attentional improvement in rats with the nicotinic agonist AZ12564698 (AZD3480)." BIOCHEMICAL PHARMACOLOGY 82.8 (October 15, 2011): 1040-1041.
Source
wos-lite
Published In
Biochemical Pharmacology
Volume
82
Issue
8
Publish Date
2011
Start Page
1040
End Page
1041
DOI
10.1016/j.bcp.2011.07.046

Using zebrafish to fill the gap between in vitro and rodent models for nicotinic drug development

Authors
Levin, ED
MLA Citation
Levin, ED. "Using zebrafish to fill the gap between in vitro and rodent models for nicotinic drug development." Biochemical Pharmacology 82.8 (October 2011): 1038-1039.
Source
crossref
Published In
Biochemical Pharmacology
Volume
82
Issue
8
Publish Date
2011
Start Page
1038
End Page
1039
DOI
10.1016/j.bcp.2011.07.040

Lorcaserin, a 5-HT2C agonist, decreases nicotine self-administration in female rats.

Lorcaserin, a selective 5-hydroxytryptamine(2C) (5-HT(2C)) agonist, has been shown to facilitate weight loss in obese populations. It was assessed for its efficacy in reducing nicotine self-administration in young adult female Sprague-Dawley rats. The effect of short-term doses (subcutaneous) on nicotine self-administration (0.03 mg/kg per infusion) with a fixed ratio 1 schedule was assessed in 3-h sessions. Short-term lorcaserin doses (0.3125-20 mg/kg) were administered in a counterbalanced order. Significant reduction of nicotine self-administration was achieved with all of the short-term doses in this range. Tests of lorcaserin on locomotor activity detected prominent sedative effects at doses greater than 1.25 mg/kg with more modest transient effects seen at 0.625 to 1.25 mg/kg. Long-term effects of lorcaserin on locomotor activity were tested with repeated injections with 0.625 mg/kg lorcaserin 10 times over 2 weeks. This low lorcaserin dose did not cause an overall change in locomotor activity relative to that of saline-injected controls. Long-term lorcaserin (0.625 mg/kg) significantly reduced nicotine self-administration over a 2-week period of repeated injections. Long-term lorcaserin at this same dose had no significant effects on food self-administration over the same 2-week period of repeated injections. These studies support development of the 5-HT(2C) agonist lorcaserin to aid tobacco smoking cessation.

Authors
Levin, ED; Johnson, JE; Slade, S; Wells, C; Cauley, M; Petro, A; Rose, JE
MLA Citation
Levin, ED, Johnson, JE, Slade, S, Wells, C, Cauley, M, Petro, A, and Rose, JE. "Lorcaserin, a 5-HT2C agonist, decreases nicotine self-administration in female rats." J Pharmacol Exp Ther 338.3 (September 2011): 890-896.
PMID
21636655
Source
pubmed
Published In
The Journal of pharmacology and experimental therapeutics
Volume
338
Issue
3
Publish Date
2011
Start Page
890
End Page
896
DOI
10.1124/jpet.111.183525

The novel, selective, brain-penetrant neuropeptide Y Y2 receptor antagonist, JNJ-31020028, tested in animal models of alcohol consumption, relapse, and anxiety.

Neuropeptide Y (NPY) signaling has been shown to modulate stress responses and to be involved in regulation of alcohol intake and dependence. The present study explores the possibility that blockade of NPY Y2 autoreceptors using a novel, blood-brain barrier penetrant NPY Y2 receptor antagonist, JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), may achieve a therapeutically useful activation of the NPY system in alcohol- and anxiety-related behavioral models. We examined JNJ-31020028 in operant alcohol self-administration, stress-induced reinstatement to alcohol seeking, and acute alcohol withdrawal (hangover)-induced anxiety. Furthermore, we tested its effects on voluntary alcohol consumption in a genetic animal model of alcohol preference, the alcohol-preferring (P) rat. Neither systemic (0, 15, 30, and 40 mg/kg, subcutaneously [s.c.]) nor intracerebroventricular (0.0, 0.3, and 1.0 nmol/rat) administration of JNJ-31020028 affected alcohol-reinforced lever pressing or relapse to alcohol seeking behavior following stress exposure. Also, when its effects were tested on unlimited access to alcohol in P rats, preference for alcohol solution was transiently suppressed but without affecting voluntary alcohol intake. JNJ-31020028 (15 mg/kg, s.c.) did reverse the anxiogenic effects of withdrawal from a single bolus dose of alcohol on the elevated plus-maze, confirming the anxiolytic-like properties of NPY Y2 antagonism. Our data do not support Y2 antagonism as a mechanism for reducing alcohol consumption or relapse-like behavior, but the observed effects on withdrawal-induced anxiety suggest that NPY Y2 receptor antagonists may be a putative treatment for the negative affective states following alcohol withdrawal.

Authors
Cippitelli, A; Rezvani, AH; Robinson, JE; Eisenberg, L; Levin, ED; Bonaventure, P; Motley, ST; Lovenberg, TW; Heilig, M; Thorsell, A
MLA Citation
Cippitelli, A, Rezvani, AH, Robinson, JE, Eisenberg, L, Levin, ED, Bonaventure, P, Motley, ST, Lovenberg, TW, Heilig, M, and Thorsell, A. "The novel, selective, brain-penetrant neuropeptide Y Y2 receptor antagonist, JNJ-31020028, tested in animal models of alcohol consumption, relapse, and anxiety." Alcohol 45.6 (September 2011): 567-576.
PMID
21145691
Source
pubmed
Published In
Alcohol
Volume
45
Issue
6
Publish Date
2011
Start Page
567
End Page
576
DOI
10.1016/j.alcohol.2010.09.003

Attention-modulating effects of cognitive enhancers.

Attention can be readily measured in experimental animal models. Animal models of attention have been used to better understand the neural systems involved in attention, how attention is impaired, and how therapeutic treatments can ameliorate attentional deficits. This review focuses on the ways in which animal models are used to better understand the neuronal mechanism of attention and how to develop new therapeutic treatments for attentional impairment. Several behavioral test methods have been developed for experimental animal studies of attention, including a 5-choice serial reaction time task (5-CSRTT), a signal detection task (SDT), and a novel object recognition (NOR) test. These tasks can be used together with genetic, lesion, pharmacological and behavioral models of attentional impairment to test the efficacy of novel therapeutic treatments. The most prominent genetic model is the spontaneously hypertensive rat (SHR). Well-characterized lesion models include frontal cortical or hippocampal lesions. Pharmacological models include challenge with the NMDA glutamate antagonist dizocilpine (MK-801), the nicotinic cholinergic antagonist mecamylamine and the muscarinic cholinergic antagonist scopolamine. Behavioral models include distracting stimuli and attenuated target stimuli. Important validation of these behavioral tests and models of attentional impairments for developing effective treatments for attentional dysfunction is the fact that stimulant treatments effective for attention deficit hyperactivity disorder (ADHD), such as methylphenidate (Ritalin®), are effective in the experimental animal models. Newer lines of treatment including nicotinic agonists, α4β2 nicotinic receptor desensitizers, and histamine H₃ antagonists, have also been found to be effective in improving attention in these animal models. Good carryover has also been seen for the attentional improvement caused by nicotine in experimental animal models and in human populations. Animal models of attention can be effectively used for the development of new treatments of attentional impairment in ADHD and other syndromes in which have attentional impairments occur, such as Alzheimer's disease and schizophrenia.

Authors
Levin, ED; Bushnell, PJ; Rezvani, AH
MLA Citation
Levin, ED, Bushnell, PJ, and Rezvani, AH. "Attention-modulating effects of cognitive enhancers." Pharmacol Biochem Behav 99.2 (August 2011): 146-154. (Review)
PMID
21334367
Source
pubmed
Published In
Pharmacology, Biochemistry and Behavior
Volume
99
Issue
2
Publish Date
2011
Start Page
146
End Page
154
DOI
10.1016/j.pbb.2011.02.008

Role of individual and developmental differences in voluntary cocaine intake in rats.

RATIONALE: Early-onset drug taking is associated with increased likelihood of addiction, but it is unclear whether early onset is causal in development of addiction. Many other factors are associated with increased risk of addiction and also promote early intake. Here, a rodent model is used to explore the causality of early onset in development of self-administration and addiction-like behavior and to examine factors that promote self-administration. METHODS: We used cocaine self-administration to examine drug taking and addiction-like behavior in adolescent and adult rats a priori characterized for their locomotor responses to novelty and cocaine and behavior in the light-dark task. RESULTS: Adolescent animals initially sought more cocaine than adults. However, as the adolescents matured, their intake fell and they did not differ from adults in terms of unreinforced lever-pressing, extinction or reinstatement behavior. For both age groups, self-administration was positively correlated with the locomotor response to novelty, the locomotor response to cocaine, and with time in light in the light-dark task. The rats that were insensitive to cocaine's locomotor effects and that spent the least time in light in the light-dark task sought the least cocaine, appearing to be "protected" from the reinforcing effects of cocaine. There was no difference between the two age groups in appearance of this "protected" phenotype. CONCLUSIONS: These results suggest that early onset of drug taking may promote increased use, but does not promote progression to addiction-like behavior. Furthermore, protective factors, such as innate anxiety and insensitivity to cocaine's pharmacological effects, function across developmental stages.

Authors
Schramm-Sapyta, NL; Cauley, MC; Stangl, DK; Glowacz, S; Stepp, KA; Levin, ED; Kuhn, CM
MLA Citation
Schramm-Sapyta, NL, Cauley, MC, Stangl, DK, Glowacz, S, Stepp, KA, Levin, ED, and Kuhn, CM. "Role of individual and developmental differences in voluntary cocaine intake in rats." Psychopharmacology (Berl) 215.3 (June 2011): 493-504.
PMID
21347641
Source
pubmed
Published In
Psychopharmacology
Volume
215
Issue
3
Publish Date
2011
Start Page
493
End Page
504
DOI
10.1007/s00213-011-2216-5

Sazetidine-A, a selective α4β2 nicotinic acetylcholine receptor ligand: effects on dizocilpine and scopolamine-induced attentional impairments in female Sprague-Dawley rats.

BACKGROUND: Neuronal nicotinic receptor systems have been shown to play key roles in cognition. Nicotine and nicotinic analogs improve attention and nicotinic antagonists impair it. This study was conducted to investigate the role of α4β2 nicotinic receptors in sustained attention using a novel selective α4β2 nicotinic receptor ligand, sazetidine-A. METHODS: Female rats were trained to perform the signal detection task to a stable baseline of accuracy. The rats were injected with saline, sazetidine-A (0.01, 0.03, and 0.1 mg/kg), dizocilpine (0.05 mg/kg), or their combination; or, in another experiment, the rats were injected with the same doses of sazetidine-A, scopolamine (0.02 mg/kg), or their combination. RESULTS: Percent hit and percent correct rejection showed that dizocilpine caused significant (p < 0.025) impairments in performance, which were significantly reversed by each of the sazetidine-A doses. Response omissions were significantly (p < 0.05) increased by dizocilpine, and this was also significantly reversed by each of the sazetidine-A doses. None of the sazetidine-A doses had significant effects on hit, correct rejection, or response omissions when given alone. Scopolamine also caused significant (p < 0.0005) impairments in percent hit and percent correct rejection and increased response omissions, which were significantly attenuated by all the sazetidine-A doses for percent hit and response omissions and by the highest dose of sazetidine-A for percent correct rejection. Both scopolamine and dizocilpine significantly (p < 0.0005) increased response latency, an effect which was significantly attenuated by sazetidine-A coadministration. CONCLUSIONS: These studies imply an important role for α4β2 nicotinic receptors in improving sustained attention under conditions that disrupt it. Very low doses of sazetidine-A or drugs with a similar profile may provide therapeutic benefit for reversing attentional impairment in patients suffering from mental disorders and/or cognitive impairment.

Authors
Rezvani, AH; Cauley, M; Sexton, H; Xiao, Y; Brown, ML; Paige, MA; McDowell, BE; Kellar, KJ; Levin, ED
MLA Citation
Rezvani, AH, Cauley, M, Sexton, H, Xiao, Y, Brown, ML, Paige, MA, McDowell, BE, Kellar, KJ, and Levin, ED. "Sazetidine-A, a selective α4β2 nicotinic acetylcholine receptor ligand: effects on dizocilpine and scopolamine-induced attentional impairments in female Sprague-Dawley rats." Psychopharmacology (Berl) 215.4 (June 2011): 621-630.
PMID
21274704
Source
pubmed
Published In
Psychopharmacology
Volume
215
Issue
4
Publish Date
2011
Start Page
621
End Page
630
DOI
10.1007/s00213-010-2161-8

EFFECTS OF A NOVEL, SELECTIVE BRAIN NPY Y2 RECPTOR ANATONIST JNJ-31020028, ON ALCOHOL CONSUMPTION, RELAPSE AND ANXIETY IN RATS

Authors
Rezvani, AH; Robinson, E; Eisenberg, L; Levin, ED; Bonaventure, P; Motley, T; Lovenberg, TW; Heilig, M; Thorsell, A; Cippitelli, A
MLA Citation
Rezvani, AH, Robinson, E, Eisenberg, L, Levin, ED, Bonaventure, P, Motley, T, Lovenberg, TW, Heilig, M, Thorsell, A, and Cippitelli, A. "EFFECTS OF A NOVEL, SELECTIVE BRAIN NPY Y2 RECPTOR ANATONIST JNJ-31020028, ON ALCOHOL CONSUMPTION, RELAPSE AND ANXIETY IN RATS." June 2011.
Source
wos-lite
Published In
Alcoholism: Clinical and Experimental Research
Volume
35
Issue
6
Publish Date
2011
Start Page
68A
End Page
68A

JNJ-39220675, a novel selective histamine H3 receptor antagonist, reduces the abuse-related effects of alcohol in rats.

RATIONALE: A few recent studies suggest that brain histamine levels and signaling via H(3) receptors play an important role in modulation of alcohol stimulation and reward in rodents. OBJECTIVE: The present study characterized the effects of a novel, selective, and brain penetrant H(3) receptor antagonist (JNJ-39220675) on the reinforcing effects of alcohol in rats. METHODS: The effect of JNJ-39220675 on alcohol intake and alcohol relapse-like behavior was evaluated in selectively bred alcohol-preferring (P) rats using the standard two-bottle choice method. The compound was also tested on operant alcohol self administration in non-dependent rats and on alcohol-induced ataxia using the rotarod apparatus. In addition, alcohol-induced dopamine release in the nucleus accumbens was tested in freely moving rats. RESULTS: Subcutaneous administration of the selective H(3) receptor antagonist dose-dependently reduced both alcohol intake and preference in alcohol-preferring rats. JNJ-39220675 also reduced alcohol preference in the same strain of rats following a 3-day alcohol deprivation. The compound significantly and dose-dependently reduced alcohol self-administration without changing saccharin self-administration in alcohol non-dependent rats. Furthermore, the compound did not change the ataxic effects of alcohol, alcohol elimination rate, nor alcohol-induced dopamine release in nucleus accumbens. CONCLUSIONS: These results indicate that blockade of H(3) receptor should be considered as a new attractive mechanism for the treatment of alcoholism.

Authors
Galici, R; Rezvani, AH; Aluisio, L; Lord, B; Levin, ED; Fraser, I; Boggs, J; Welty, N; Shoblock, JR; Motley, ST; Letavic, MA; Carruthers, NI; Dugovic, C; Lovenberg, TW; Bonaventure, P
MLA Citation
Galici, R, Rezvani, AH, Aluisio, L, Lord, B, Levin, ED, Fraser, I, Boggs, J, Welty, N, Shoblock, JR, Motley, ST, Letavic, MA, Carruthers, NI, Dugovic, C, Lovenberg, TW, and Bonaventure, P. "JNJ-39220675, a novel selective histamine H3 receptor antagonist, reduces the abuse-related effects of alcohol in rats." Psychopharmacology (Berl) 214.4 (April 2011): 829-841.
PMID
21086115
Source
pubmed
Published In
Psychopharmacology
Volume
214
Issue
4
Publish Date
2011
Start Page
829
End Page
841
DOI
10.1007/s00213-010-2092-4

D-cycloserine selectively decreases nicotine self-administration in rats with low baseline levels of response.

Expanding the variety of treatments available to aid smoking cessation will allow the treatments to be customized to particular types of smokers. The key is to understand which subpopulations of smokers respond best to which treatment. This study used adult female Sprague-Dawley rats to evaluate the efficacy of D-cycloserine, a partial NMDA glutamate receptor agonist, in reducing nicotine self-administration. Rats were trained to self-administer nicotine (0.03 mg/kg/infusion, i.v.) via operant lever response (FR1) with a secondary visual reinforcer. Two studies of D-cycloserine effects on nicotine self-administration were conducted: an acute dose-effect study (0, 10, 20 and 40 mg/kg, s.c.) and a chronic study with 40 mg/kg given before each test session for two weeks. Effects on rats with low or high pretreatment baseline levels of nicotine self-administration were assessed. In the acute study there was a significant interaction of D-cycloserine×baseline level of nicotine self-administration. In the low baseline group, 10 mg/kg D-cycloserine significantly decreased nicotine self-administration. In the high baseline group, 40 mg/kg significantly increased nicotine self-administration. In the repeated injection study, there was also a significant interaction of d-cycloserine×baseline level of nicotine self-administration. Chronic D-cycloserine significantly reduced nicotine self-administration selectively in rats with low baseline nicotine use, but was ineffective with the rats with higher levels of baseline nicotine self-administration. NMDA glutamate treatments may be particularly useful in helping lighter smokers successfully quit smoking, highlighting the need for diverse treatments for different types of smokers.

Authors
Levin, ED; Slade, S; Wells, C; Petro, A; Rose, JE
MLA Citation
Levin, ED, Slade, S, Wells, C, Petro, A, and Rose, JE. "D-cycloserine selectively decreases nicotine self-administration in rats with low baseline levels of response." Pharmacol Biochem Behav 98.2 (April 2011): 210-214.
PMID
21192967
Source
pubmed
Published In
Pharmacology, Biochemistry and Behavior
Volume
98
Issue
2
Publish Date
2011
Start Page
210
End Page
214
DOI
10.1016/j.pbb.2010.12.023

Silver exposure in developing zebrafish produces persistent synaptic and behavioral changes.

Environmental silver exposures are increasing due to the use of silver nanoparticles, which exert antimicrobial actions by releasing Ag+, a suspected developmental neurotoxicant. We evaluated the long-term neurochemical and behavioral effects of embryonic Ag+ exposure in zebrafish at concentrations that had no overt effects on morphological development. Exposure to 0.03, 0.1 or 0.3 μM Ag+ during the first five days post-fertilization caused elevations in both dopamine and serotonin turnover in the adult zebrafish brain without affecting basal neurotransmitter levels. Consistent with these synaptic effects, Ag+-exposed fish showed a faster acquisition of avoidance behavior in a three-chamber test apparatus, without any change in response latency or overall swimming ability. Our results indicate that Ag+ is a developmental neurotoxicant that causes persistent neurobehavioral effects, reinforcing health concerns about Ag+ released from silver nanoparticles.

Authors
Powers, CM; Levin, ED; Seidler, FJ; Slotkin, TA
MLA Citation
Powers, CM, Levin, ED, Seidler, FJ, and Slotkin, TA. "Silver exposure in developing zebrafish produces persistent synaptic and behavioral changes." Neurotoxicol Teratol 33.2 (March 2011): 329-332.
PMID
21035540
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
33
Issue
2
Publish Date
2011
Start Page
329
End Page
332
DOI
10.1016/j.ntt.2010.10.006

Histamine H(1) antagonist treatment with pyrilamine reduces nicotine self-administration in rats.

Nicotine has been definitively shown to be critically involved in the neural bases of tobacco addiction. However, nicotine releases a wide variety of neurotransmitters. Nicotine-induced dopamine release has been shown to play a key role in facilitating nicotine self-administration. Other transmitter systems may also play important roles in the pharmacological effects of nicotine and may provide important leads for combating nicotine self-administration. Clozapine, an antipsychotic drug, which blocks a variety of different transmitter receptors including serotonin 5HT(2) and histamine H(1) receptors, has been found to decrease smoking. Previously we found that the serotonin 5HT(2) antagonist, ketanserin, significantly reduced nicotine self-administration. In the current study, we assessed histamine H(1) receptor interaction with nicotine self-administration. Young adult female Sprague-Dawley rats were fitted with IV catheters and trained to self-administer nicotine (0.03mg/kg/infusion). Acute doses of 40mg/kg of pyrilamine, a histamine H(1) antagonist, significantly reduced nicotine self-administration. We also found that repeated injections (20mg/kg) or chronic infusion via osmotic minipumps (50mg/kg/day) of pyrilamine also significantly decreased nicotine self-administration. The peripherally restricted H(1) antagonist ebastine was ineffective in reducing nicotine self-administration, pointing to central H(1) receptor blockade as key for the effectiveness of pyrilamine. H(1) antagonists may be a promising avenue to explore for new treatments to aid smoking cessation.

Authors
Levin, ED; Slade, S; Wells, C; Pruitt, M; Cousins, V; Cauley, M; Petro, A; Hampton, D; Rose, J
MLA Citation
Levin, ED, Slade, S, Wells, C, Pruitt, M, Cousins, V, Cauley, M, Petro, A, Hampton, D, and Rose, J. "Histamine H(1) antagonist treatment with pyrilamine reduces nicotine self-administration in rats." Eur J Pharmacol 650.1 (January 10, 2011): 256-260.
PMID
20951696
Source
pubmed
Published In
European Journal of Pharmacology
Volume
650
Issue
1
Publish Date
2011
Start Page
256
End Page
260
DOI
10.1016/j.ejphar.2010.10.013

Differing Effects of 3 Organophosphates (Chlorpyrifos, Diazinon and Parathion) on Developing Zebrafish Nervous System

Authors
Yen, J; Donerly, S; Levin, E; Linney, E
MLA Citation
Yen, J, Donerly, S, Levin, E, and Linney, E. "Differing Effects of 3 Organophosphates (Chlorpyrifos, Diazinon and Parathion) on Developing Zebrafish Nervous System." 2011.
Source
wos-lite
Published In
Neurotoxicology and Teratology
Volume
33
Issue
4
Publish Date
2011
Start Page
509
End Page
510
DOI
10.1016/j.ntt.2011.05.062

Zebrafish assessment of cognitive improvement and anxiolysis: filling the gap between in vitro and rodent models for drug development.

Zebrafish can provide a valuable animal model to screen potential cognitive enhancing and anxiolytic drugs. They are economical and can provide a relatively quick indication of possible functional efficacy. In as much as they have a complex nervous system and elaborate behavioral repertoire, zebrafish can provide a good intermediate model between in vitro receptor and cell-based assays and classic mammalian models for drug screening. In addition, the variety of molecular tools available in zebrafish makes them outstanding models for helping to determine the neuromolecular mechanisms for psychoactive drugs. However, to use zebrafish as a translational model we must have validated, sensitive and efficient behavioral tests. In a series of studies, our lab has developed tests of cognitive function and stress response, which are sensitive to drug effects in a similar manner as rodent models and humans for cognitive enhancement and alleviating stress response. In particular, the three-chamber task for learning and memory was shown to be sensitive to the cognitive enhancing effects of nicotine and has been useful in helping to determine neural mechanisms crucial for nicotinic-induced cognitive enhancement. The novel tank diving test was shown to be a valid and efficient test of stress response. It is sensitive to the reduction in stress-related behaviors due to the amxiolytic drugs diazepam and buspirone but not chlordiazepoxide. Nicotine also causes stress alleviating effects which can be interpreted as anxiolytic effects. Zebrafish models of behavioral pharmacology can be useful to efficiently screen test compounds for drug development and can be useful in helping to determine the mechanisms crucial for new therapeutic treatments of neurobehavioral impairments.

Authors
Levin, ED
MLA Citation
Levin, ED. "Zebrafish assessment of cognitive improvement and anxiolysis: filling the gap between in vitro and rodent models for drug development." Rev Neurosci 22.1 (2011): 75-84.
PMID
21615262
Source
pubmed
Published In
Reviews in the neurosciences
Volume
22
Issue
1
Publish Date
2011
Start Page
75
End Page
84
DOI
10.1515/RNS.2011.009

Nicotinic receptor systems and neurobehavioral function in zebrafish

Nicotinic acetylcholine receptors appear to be quite ancient phylogenetically and are used in the nervous systems of a great number of species across broad parts of the animal kingdom. They play important roles in a variety of neurobehavioral functions from neuromuscular activation to cognitive function. Nicotinic receptor function is an excellent field in which to assess the potential commonalities of neurobehavioral functions across animal species. Nicotinic receptors are remarkably consistent across species and the behavioral effects of nicotinic treatments have been very well determined in mammals. Since zebrafish are an emerging aquatic model for studying neurobehavioral function, we have determined the effects of nicotine, the prototypic nicotinic agonist as well as nicotinic antagonists on cognitive function, exploratory behavior and stress response in a series of behavioral tests we have developed to reliably index these behavioral functions. The overall hypothesis of this line of investigation was that nicotine would have similar behavioral effects in zebrafish as in mammals when analogous tests of behavioral function are used. As with mammalian species, nicotine significantly improves learning and memory at low to moderate doses in zebrafish with an inverted J-shaped dose-effect function. The nicotine-induced learning improvement in zebrafish is reversed with the nicotinic antagonist mecamylamine and is accompanied by increased brain dopamine metabolite levels, an effect which is also reversed with mecamylamine. Also, as in mammals, nicotine has anxiolytic effects in zebrafish. Nicotine significantly reduces bottom dwelling in the novel tank diving task. This effect is reversed by either α7 or α4β2 nicotinic antagonist coadministration. In many respects nicotine has similar effects in zebrafish as in rodents and humans. These studies point to the value of zebrafish as models of human neurobehavioral function. © 2011 Springer Science+Business Media, LLC.

Authors
Levin, ED
MLA Citation
Levin, ED. "Nicotinic receptor systems and neurobehavioral function in zebrafish." Neuromethods 52 (2011): 89-100.
Source
scival
Published In
Neuromethods
Volume
52
Publish Date
2011
Start Page
89
End Page
100
DOI
10.1007/978-1-60761-922-2_4

PPI deficit induced by amphetamine is attenuated by the histamine H1 antagonist pyrilamine, but is exacerbated by the serotonin 5-HT2 antagonist ketanserin.

RATIONALE: Prepulse inhibition (PPI) of the startle response is a classic model of sensorimotor gating. Robust PPI impairments can be induced by dopamine agonists such as the indirect agonist amphetamine. The antipsychotic clozapine can attenuate PPI impairment induced by dopamine agonists. Clozapine is a complex drug with antagonistic effects on a variety of receptors, including serotonin and histamine. The relative contribution of its component actions to its efficacy is still unclear. OBJECTIVES: To better characterize the role of histamine and serotonin receptors in the modulation of PPI in rats, we studied the effects of the H(1) histamine antagonist pyrilamine (10, 20, and 40 mg/kg) on amphetamine-induced (1 mg/kg) PPI deficits (Experiment 1); and the interaction of pyrilamine (20 mg/kg) with the 5-HT(2) antagonist ketanserin (1 and 2 mg/kg) on the amphetamine-induced PPI disruption (Experiment 2). METHODS: Tactile startle stimuli consisted of 30 PSI air-puffs. Three acoustic prepulse intensity levels were used: 68, 71, and 77 dB, presented on a 65-dB background noise. In both experiments, all animals received all drug doses and combinations with different counterbalanced orders. RESULTS: Pyrilamine (20 mg/kg) was effective in counteracting the PPI impairment caused by amphetamine administration, whereas ketanserin exacerbated the amphetamine-induced PPI deficit. CONCLUSIONS: Based on its ability to reverse amphetamine-induced PPI deficits, blockade of histamine H(1) receptors seems to contribute to the therapeutic effect of the antipsychotic clozapine. Serotonin 5-HT(2)-receptor blockade, though, does not appear to contribute to this effect, and may in fact detract from it.

Authors
Larrauri, JA; Levin, ED
MLA Citation
Larrauri, JA, and Levin, ED. "PPI deficit induced by amphetamine is attenuated by the histamine H1 antagonist pyrilamine, but is exacerbated by the serotonin 5-HT2 antagonist ketanserin." Psychopharmacology (Berl) 212.4 (December 2010): 551-558.
PMID
20811878
Source
pubmed
Published In
Psychopharmacology
Volume
212
Issue
4
Publish Date
2010
Start Page
551
End Page
558
DOI
10.1007/s00213-010-2005-6

Effects of sazetidine-A, a selective alpha4beta2 nicotinic acetylcholine receptor desensitizing agent on alcohol and nicotine self-administration in selectively bred alcohol-preferring (P) rats.

RATIONALE: Manipulations of nicotinic cholinergic receptors have been shown to influence both alcohol and nicotine intake. Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a novel compound that potently and selectively desensitizes alpha4beta2 nicotinic receptors with only modest receptor activation. OBJECTIVES: The goal of the present study was to examine the effects of sazetidine-A on alcohol and nicotine self-administration in alcohol-preferring (P) rats. METHODS: P rats were given the choice of water or alcohol. Once stable baselines were established, the acute (0, 0.1, 0.3, 1, and 3 mg/kg, s.c.) and chronic (3 mg/kg for 10 days) effects of sazetidine-A on alcohol intake were assessed. Naltrexone (2.5 mg/kg) served as a positive control. The effect of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on saccharin (0.2%) preference was also assessed. In addition, the acute effects of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on alcohol intake after alcohol deprivation were evaluated. In another experiment, the effects of sazetidine-A (0, 1, or 3 mg/kg) on i.v. nicotine self-administration in P and NP rats were assessed. RESULTS: Sazetidine-A caused a dose-dependent reduction in alcohol intake. Chronic sazetidine-A also effectively reduced alcohol intake until the seventh day of treatment, when partial tolerance appeared to develop. In the post-deprivation study, sazetidine-A significantly reduced alcohol intake and preference. Sazetidine-A at 3 mg/kg significantly reduced nicotine self-administration in both lines. CONCLUSIONS: Sazetidine-A significantly reduced alcohol and nicotine intake in P rats that self-administer higher levels of both drugs. Sazetidine-A may hold promise for the treatment of alcohol and nicotine addiction.

Authors
Rezvani, AH; Slade, S; Wells, C; Petro, A; Lumeng, L; Li, T-K; Xiao, Y; Brown, ML; Paige, MA; McDowell, BE; Rose, JE; Kellar, KJ; Levin, ED
MLA Citation
Rezvani, AH, Slade, S, Wells, C, Petro, A, Lumeng, L, Li, T-K, Xiao, Y, Brown, ML, Paige, MA, McDowell, BE, Rose, JE, Kellar, KJ, and Levin, ED. "Effects of sazetidine-A, a selective alpha4beta2 nicotinic acetylcholine receptor desensitizing agent on alcohol and nicotine self-administration in selectively bred alcohol-preferring (P) rats." Psychopharmacology (Berl) 211.2 (August 2010): 161-174.
PMID
20535453
Source
pubmed
Published In
Psychopharmacology
Volume
211
Issue
2
Publish Date
2010
Start Page
161
End Page
174
DOI
10.1007/s00213-010-1878-8

NICOTINE SELF-ADMINISTRATION IN SELECTIVELY-BRED ALCOHOL PREFERRING (P) RATS: NICOTINIC INVOLVEMENT

Authors
Rezvani, AH; Lumeng, L; Li, TK; Xiao, Y; Brown, ML; Paige, MA; McDowell, BE; Rose, JE; Kellar, KJ; Levin, ED
MLA Citation
Rezvani, AH, Lumeng, L, Li, TK, Xiao, Y, Brown, ML, Paige, MA, McDowell, BE, Rose, JE, Kellar, KJ, and Levin, ED. "NICOTINE SELF-ADMINISTRATION IN SELECTIVELY-BRED ALCOHOL PREFERRING (P) RATS: NICOTINIC INVOLVEMENT." June 2010.
Source
wos-lite
Published In
Alcoholism: Clinical and Experimental Research
Volume
34
Issue
6
Publish Date
2010
Start Page
18A
End Page
18A

Persistent high alcohol consumption in alcohol-preferring (P) rats results from a lack of normal aversion to alcohol.

AIMS: In this study, we tested the impact of pretreatment with alcohol on subsequent alcohol drinking in outbred Sprague-Dawley and selectively bred alcohol-preferring (P) rats. METHODS: As a pretreatment, male Sprague-Dawley and P rats were given a passive oral administration of either alcohol (1.0 g/kg) or tap water. Then, they were given free choice of drinking alcohol (5% v/v) or water in their home cages, which was measured over 4 weeks. RESULTS: Without alcohol pretreatment, there was no significant strain difference in alcohol preference; both strains preferred 5% (v/v) alcohol solution. The strain difference was only apparent in the groups given alcohol pretreatment. This arose from the fact that alcohol pretreatment significantly reduced alcohol preference in the Sprague-Dawley rats to a level well below 50%, while it did not alter drinking behavior in P rats. The same effects were seen with total alcohol consumption (g/kg/day). These effects persisted throughout the 4 weeks of the study. CONCLUSIONS: The principal difference between the Sprague-Dawley and P rats was that the P rats did not show the normal aversion to alcohol after forced exposure to alcohol that the Sprague-Dawley rats showed. One of the potential contributors to high alcohol intake and preference in P rats may be lack of sensitivity to aversive effects of alcohol.

Authors
Rezvani, AH; Sexton, H; Levin, ED
MLA Citation
Rezvani, AH, Sexton, H, and Levin, ED. "Persistent high alcohol consumption in alcohol-preferring (P) rats results from a lack of normal aversion to alcohol." Alcohol Alcohol 45.3 (May 2010): 219-222.
PMID
20356869
Source
pubmed
Published In
Alcohol and Alcoholism
Volume
45
Issue
3
Publish Date
2010
Start Page
219
End Page
222
DOI
10.1093/alcalc/agq020

Neonatal parathion exposure and interactions with a high-fat diet in adulthood: Adenylyl cyclase-mediated cell signaling in heart, liver and cerebellum.

Organophosphates are developmental neurotoxicants but recent evidence points to additional adverse effects on metabolism and cardiovascular function. One common mechanism is disrupted cell signaling mediated through cyclic AMP, targeting neurohumoral receptors, G-proteins and adenylyl cyclase (AC) itself. Earlier, we showed that neonatal parathion evokes later upregulation of the hepatic AC pathway in adolescence but that the effect wanes by young adulthood; nevertheless metabolic changes resembling prediabetes persist. Here, we administered parathion to neonatal rats (postnatal days 1-4, 0.1 or 0.2 mg/kg/day), straddling the threshold for cholinesterase inhibition, but we extended the studies to much later, 5 months of age. In addition, we investigated whether metabolic challenge imposed by consuming a high-fat diet for 7 weeks would exacerbate neonatal parathion's effects. Parathion alone increased the expression or function of G(i), thus reducing AC responses to fluoride. Receptors controlling AC activity were also affected: beta-adrenergic receptors (betaARs) in skeletal muscle were increased, whereas those in the heart were decreased, and the latter also showed an elevation of m(2)-muscarinic acetylcholine receptors, which inhibit AC. The high-fat diet also induced changes in AC signaling, enhancing the hepatic AC response to glucagon while impairing the cardiac response to fluoride or forskolin, and suppressing betaARs and m(2)-muscarinic receptors; the only change in the cerebellum was a decrease in betaARs. Although there were no significant interactions between neonatal parathion exposure and a high-fat diet, their convergent effects on the same signaling cascade indicate that early OP exposure, separately or combination with dietary factors, may contribute to the worldwide increase in the incidence of obesity and diabetes.

Authors
Adigun, AA; Wrench, N; Levin, ED; Seidler, FJ; Slotkin, TA
MLA Citation
Adigun, AA, Wrench, N, Levin, ED, Seidler, FJ, and Slotkin, TA. "Neonatal parathion exposure and interactions with a high-fat diet in adulthood: Adenylyl cyclase-mediated cell signaling in heart, liver and cerebellum." Brain Res Bull 81.6 (April 5, 2010): 605-612.
PMID
20074626
Source
pubmed
Published In
Brain Research Bulletin
Volume
81
Issue
6
Publish Date
2010
Start Page
605
End Page
612
DOI
10.1016/j.brainresbull.2010.01.003

Early postnatal parathion exposure in rats causes sex-selective cognitive impairment and neurotransmitter defects which emerge in aging.

Developmental exposure of rats to the organophosphate (OP) pesticides leads to altered neurobehavioral function in juvenile and young adult stages. The current study was conducted to determine whether effects of neonatal parathion exposure on cognitive performance persist in older adult and aged rats, and the relationship of behavioral changes to underlying cholinergic and serotonergic mechanisms. We administered parathion to rat pups on postnatal days 1-4, at doses spanning the threshold for the initial signs of systemic toxicity and for barely detectable cholinesterase inhibition (0.1 or 0.2 mg/kg/day). Beginning at 14 months of age and continuing until 19 months, the rats were trained in the 16-arm radial maze. Controls showed the normal sex difference in this spatial learning and memory task, with the males committing significantly fewer working memory errors than females. Neonatal parathion exposure eliminated the sex difference primarily by causing impairment in males. In association with the effects on cognitive performance, neonatal parathion exposure elicited widespread abnormalities in indices of serotonergic (5HT) and cholinergic synaptic function, characterized by upregulation of 5HT(2) receptors and the 5HT transporter, deficits in choline acetyltransferase activity and nicotinic cholinergic receptors, and increases in hemicholinium-3 binding to the presynaptic choline transporter. Within-animal correlations between behavior and neurochemistry indicated a specific correlation between working memory performance and hippocampal hemicholinium-3 binding; parathion exposure eliminated this relationship. Like the behavioral effects, males showed greater effects of parathion on neurochemical parameters. This study demonstrates the sex-selective, long-term behavioral alterations caused by otherwise nontoxic neonatal exposure to parathion, with effects increasingly expressed with aging.

Authors
Levin, ED; Timofeeva, OA; Yang, L; Petro, A; Ryde, IT; Wrench, N; Seidler, FJ; Slotkin, TA
MLA Citation
Levin, ED, Timofeeva, OA, Yang, L, Petro, A, Ryde, IT, Wrench, N, Seidler, FJ, and Slotkin, TA. "Early postnatal parathion exposure in rats causes sex-selective cognitive impairment and neurotransmitter defects which emerge in aging." Behav Brain Res 208.2 (April 2, 2010): 319-327.
PMID
20015457
Source
pubmed
Published In
Behavioural Brain Research
Volume
208
Issue
2
Publish Date
2010
Start Page
319
End Page
327
DOI
10.1016/j.bbr.2009.11.007

Nicotinic receptors in the habenula: importance for memory.

The habenula is an epithalamic structure through which descending connections pass from the telencephalon to the brainstem, putting it in a key location to provide feedback control over the brainstem monoaminergic projections ascending to the telencephalon. Habenular nuclei lesions have been shown to impair memory function. The habenular nuclei have high concentrations of nicotinic receptors. In this study we assessed the role of habenular nicotinic receptors for working memory. Adult female Sprague-Dawley rats were trained on a 16-arm maze to assess spatial working and reference memory. All rats had at least 18 sessions of training and then had bilateral chronic infusion cannulae placed into the lateral habenula nucleus. These cannulae were each connected to a slow delivery osmotic minipump that chronically infused mecamylamine 100 microg/side/day (n=9) or vehicle (aCSF) for controls (n=15) for a period of 4 weeks. Both mecamylamine-infused and control rats were acutely injected (s.c.) with nicotine (0, 0.2 or 0.4 mg/kg) in a repeated measures counterbalanced design twice at each dose during the chronic local infusion period. There was a significant (P<0.025) mecamylaminexnicotine interaction effect on memory performance. Without nicotine injection the chronic habenular mecamylamine infusion caused a significant (P<0.05) increase in total memory errors. The 0.4 mg/kg nicotine dose significantly (P<0.005) reversed the mecamylamine-induced memory impairment, returning performance back to levels seen in rats with control aCSF habenular infusions. The current study determined that nicotinic receptors in the lateral habenular nucleus are important for spatial memory function. Descending projections from the telencephalon through the habenula to brainstem nuclei using nicotinic receptors appear to be a key pathway for memory processing.

Authors
Sanders, D; Simkiss, D; Braddy, D; Baccus, S; Morton, T; Cannady, R; Weaver, N; Rose, JE; Levin, ED
MLA Citation
Sanders, D, Simkiss, D, Braddy, D, Baccus, S, Morton, T, Cannady, R, Weaver, N, Rose, JE, and Levin, ED. "Nicotinic receptors in the habenula: importance for memory." Neuroscience 166.2 (March 17, 2010): 386-390.
PMID
20034548
Source
pubmed
Published In
Neuroscience
Volume
166
Issue
2
Publish Date
2010
Start Page
386
End Page
390
DOI
10.1016/j.neuroscience.2009.12.035

Sazetidine-A, a selective alpha4beta2 nicotinic receptor desensitizing agent and partial agonist, reduces nicotine self-administration in rats.

Adequate treatment of tobacco addiction remains problematic. Part of the problem with treatment is a poor understanding of the pharmacologic aspects of nicotine contributing to addiction. In addition to activating nicotinic acetylcholine receptors, nicotine also desensitizes them. It is currently not known how much of each of nicotine's actions contribute to its particular behavioral effects. Sazetidine-A (saz-A) is a novel nicotinic receptor-desensitizing agent and partial agonist with high selectivity for alpha4beta2 receptors. The current experiments were conducted to determine whether saz-A would reduce nicotine self-administration in rats and to characterize its ancillary effects. Adult male Sprague-Dawley rats were allowed to self-administer nicotine. After initial food pellet training followed by 10 sessions of nicotine self-administration training, the rats were administered saz-A (0.1-3 mg/kg s.c.) or the saline vehicle in a repeated-measures counterbalanced design. Saz-A at the 3 mg/kg dose significantly decreased nicotine self-administration relative to performance of the same rats after saline injections. In a second study, long-term administration of this dose of sazetidine-A over the course of 10 sessions significantly reduced nicotine self-administration with no apparent diminution of effect. Saz-A in this dose range had only modest effects on locomotor activity, without any overall decrease in activity over a 1-h-long session. Saz-A significantly reduced food self-administration, but this effect was smaller than its effect on nicotine self-administration. Saz-A, which is a selective alpha4beta2-desensitizing agent and partial agonist, effectively reduces nicotine self-administration. This type of treatment holds promise for a new therapy to aid smoking cessation.

Authors
Levin, ED; Rezvani, AH; Xiao, Y; Slade, S; Cauley, M; Wells, C; Hampton, D; Petro, A; Rose, JE; Brown, ML; Paige, MA; McDowell, BE; Kellar, KJ
MLA Citation
Levin, ED, Rezvani, AH, Xiao, Y, Slade, S, Cauley, M, Wells, C, Hampton, D, Petro, A, Rose, JE, Brown, ML, Paige, MA, McDowell, BE, and Kellar, KJ. "Sazetidine-A, a selective alpha4beta2 nicotinic receptor desensitizing agent and partial agonist, reduces nicotine self-administration in rats." J Pharmacol Exp Ther 332.3 (March 2010): 933-939.
PMID
20007754
Source
pubmed
Published In
The Journal of pharmacology and experimental therapeutics
Volume
332
Issue
3
Publish Date
2010
Start Page
933
End Page
939
DOI
10.1124/jpet.109.162073

Neonatal exposure to parathion alters lipid metabolism in adulthood: Interactions with dietary fat intake and implications for neurodevelopmental deficits.

Organophosphates are developmental neurotoxicants but recent evidence also points to metabolic dysfunction. We determined whether neonatal parathion exposure in rats has long-term effects on regulation of adipokines and lipid peroxidation. We also assessed the interaction of these effects with increased fat intake. Rats were given parathion on postnatal days 1-4 using doses (0.1 or 0.2mg/kg/day) that straddle the threshold for barely detectable cholinesterase inhibition and the first signs of systemic toxicity. In adulthood, animals were either maintained on standard chow or switched to a high-fat diet for 7 weeks. We assessed serum leptin and adiponectin, tumor necrosis factor-alpha (TNFalpha) in adipose tissues, and thiobarbituric acid reactive species (TBARS) in peripheral tissues and brain regions. Neonatal parathion exposure uncoupled serum leptin levels from their dependence on body weight, suppressed adiponectin and elevated TNFalpha in white adipose tissue. Some of the effects were offset by a high-fat diet. Parathion reduced TBARS in the adipose tissues, skeletal muscle and temporal/occipital cortex but not in heart, liver, kidney or frontal/parietal cortex; it elevated TBARS in the cerebellum; the high-fat diet again reversed many of the effects. Neonatal parathion exposure disrupts the regulation of adipokines that communicate metabolic status between adipose tissues and the brain, while also evoking an inflammatory adipose response. Our results are consistent with impaired fat utilization and prediabetes, as well as exposing a potential relationship between effects on fat metabolism and on synaptic function in the brain.

Authors
Lassiter, TL; Ryde, IT; Levin, ED; Seidler, FJ; Slotkin, TA
MLA Citation
Lassiter, TL, Ryde, IT, Levin, ED, Seidler, FJ, and Slotkin, TA. "Neonatal exposure to parathion alters lipid metabolism in adulthood: Interactions with dietary fat intake and implications for neurodevelopmental deficits." Brain Res Bull 81.1 (January 15, 2010): 85-91.
PMID
19615431
Source
pubmed
Published In
Brain Research Bulletin
Volume
81
Issue
1
Publish Date
2010
Start Page
85
End Page
91
DOI
10.1016/j.brainresbull.2009.07.002

Hippocampal infusions of MARCKS peptides impair memory of rats on the radial-arm maze.

In vitro hippocampal studies by Gay et al. (2008) demonstrated that a myristoylated alanine-rich C kinase substrate (MARCKS) peptide comprising the phosphorylation site or effector domain of the protein acts as a powerful inhibitor of alpha7 nicotinic acetylcholine receptors (nAChRs), which are known to be critically involved in memory function. However, behavioral consequences of hippocampal MARCKS peptide infusions have not been investigated. The purpose of the current study was to determine if local infusions in the rat ventral hippocampus of long (comprising amino acids 151-175) and short (amino acids 159-165) forms of MARCKS peptides could affect memory performance in the 16-arm radial maze. Our results demonstrated a dramatic impairment of both working (changing) and reference (constant) memory with MARCKS(151-175) only. The shorter MARCKS peptide did not affect memory performance. This is in line with in vitro results reported by Gay et al. (2008) that long, but not short, MARCKS peptides inhibit alpha7 nAChRs. We also found that the effect of the MARCKS(151-175) peptide was dose-dependent, with a robust memory impairment at 10 microg/side, and smaller inconsistent effects at lower doses. Our present behavioral study, together with the earlier in vitro study by Gay et al. (2008), suggests that effector domain MARCKS peptides could play a significant role in memory regulation and impairment.

Authors
Timofeeva, OA; Eddins, D; Yakel, JL; Blackshear, PJ; Levin, ED
MLA Citation
Timofeeva, OA, Eddins, D, Yakel, JL, Blackshear, PJ, and Levin, ED. "Hippocampal infusions of MARCKS peptides impair memory of rats on the radial-arm maze." Brain Res 1308 (January 13, 2010): 147-152.
PMID
19854162
Source
pubmed
Published In
Brain Research
Volume
1308
Publish Date
2010
Start Page
147
End Page
152
DOI
10.1016/j.brainres.2009.10.040

Zebrafish provide a sensitive model of persisting neurobehavioral effects of developmental chlorpyrifos exposure: comparison with nicotine and pilocarpine effects and relationship to dopamine deficits.

Chlorpyrifos (CPF) an organophosphate pesticide causes persisting behavioral dysfunction in rat models when exposure is during early development. In earlier work zebrafish were used as a complementary model to study mechanisms of CPF-induced neurotoxicity induced during early development. We found that developmental (first five days after fertilization) chlorpyrifos exposure significantly impaired learning in zebrafish. However, this testing was time and labor intensive. In the current study we tested the hypothesis that persisting effects of developmental chlorpyrifos could be detected with a brief automated assessment of startle response and that this behavioral index could be used to help determine the neurobehavioral mechanisms for persisting CPF effects. The swimming activity of adult zebrafish was assessed by a computerized video-tracking device after a sudden tap to the test arena. Ten consecutive trials (1/min) were run to determine startle response and its habituation. Additionally, habituation recovery trials were run at 8, 32 and 128 min after the end of the initial trial set. CPF-exposed fish showed a significantly (p<0.025) greater overall startle response during the 10-trial session compared to controls (group sizes: Control N=40, CPF N=24). During the initial recovery period (8 min) CPF-exposed fish showed a significantly (p<0.01) greater startle response compared to controls. To elucidate the contributions of nicotinic and muscarinic acetylcholine receptors to developmental CPF-mediated effects, the effects of developmental nicotine and pilocarpine exposure throughout the first five days after fertilization were determined. Developmental nicotine and pilocarpine exposure significantly increased startle response, though nicotine (group sizes: Control N=32, 15 mM N=12, 25 mM N=20) was much more potent than pilocarpine (group sizes: Control N=20, 100 microM N=16, 1000 microM N=12). Neither was as potent as CPF for developmental exposure increasing startle response in adulthood. Lastly, developmental CPF exposure decreased dopamine and serotonin levels and increased transmitter turnover in developing zebrafish larvae (N=4 batches of 50 embryos/treatment). Only the decline in dopamine concentrations persisted into adulthood (group sizes: Control N=14, CPF N=13). This study shows that a quick automated test of startle can detect persisting neurobehavioral impairments caused by developmental exposure to CPF. This may be helpful in screening for persisting neurobehavioral defects from a variety of toxicants.

Authors
Eddins, D; Cerutti, D; Williams, P; Linney, E; Levin, ED
MLA Citation
Eddins, D, Cerutti, D, Williams, P, Linney, E, and Levin, ED. "Zebrafish provide a sensitive model of persisting neurobehavioral effects of developmental chlorpyrifos exposure: comparison with nicotine and pilocarpine effects and relationship to dopamine deficits." Neurotoxicol Teratol 32.1 (January 2010): 99-108.
PMID
19268529
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
32
Issue
1
Publish Date
2010
Start Page
99
End Page
108
DOI
10.1016/j.ntt.2009.02.005

Gene-environment interactions: Neurodegeneration in non-mammals and mammals

The understanding of how environmental exposures interact with genetics in central nervous system dysfunction has gained great momentum in the last decade. Seminal findings have been uncovered in both mammalian and non-mammalian model in large result of the extraordinary conservation of both genetic elements and differentiation processes between mammals and non-mammalians. Emerging model organisms, such as the nematode and zebrafish have made it possible to assess the effects of small molecules rapidly, inexpensively, and on a miniaturized scale. By combining the scale and throughput of in vitro screens with the physiological complexity and traditional animal studies, these models are providing relevant information on molecular events in the etiology of neurodegenerative disorders. The utility of these models is largely driven by the functional conservation seen between them and higher organisms, including humans so that knowledge obtained using non-mammalian model systems can often provide a better understanding of equivalent processes, pathways, and mechanisms in man. Understanding the molecular events that trigger neurodegeneration has also greatly relied upon the use of tissue culture models. The purpose of this summary is to provide-state-of-the-art review of recent developments of non-mammalian experimental models and their utility in addressing issues pertinent to neurotoxicity (Caenorhabditis elegans and Danio rerio). The synopses by Aschner and Levin summarize how genetic mutants of these species can be used to complement the understanding of molecular and cellular mechanisms associated with neurobehavioral toxicity and neurodegeneration. Next, studies by Suñol and Olopade detail the predictive value of cultures in assessing neurotoxicity. Suñol and colleagues summarize present novel information strategies based on in vitro toxicity assays that are predictive of cellular effects that can be extrapolated to effects on individuals. Olopade and colleagues describe cellular changes caused by sodium metavanadate (SMV) and demonstrate how rat primary astrocyte cultures can be used as predicitive tools to assess the neuroprotective effects of antidotes on vanadium-induced astrogliosis and demyelination. © 2010 Elsevier Inc.

Authors
Aschner, M; Levin, ED; Suñol, C; Olopade, JO; Helmcke, KJ; Avila, DS; Sledge, D; Ali, RH; Upchurch, L; Donerly, S; Linney, E; Forsby, A; Ponnuru, P; Connor, JR
MLA Citation
Aschner, M, Levin, ED, Suñol, C, Olopade, JO, Helmcke, KJ, Avila, DS, Sledge, D, Ali, RH, Upchurch, L, Donerly, S, Linney, E, Forsby, A, Ponnuru, P, and Connor, JR. "Gene-environment interactions: Neurodegeneration in non-mammals and mammals." NeuroToxicology 31.5 (2010): 582-588.
PMID
20359493
Source
scival
Published In
NeuroToxicology
Volume
31
Issue
5
Publish Date
2010
Start Page
582
End Page
588
DOI
10.1016/j.neuro.2010.03.008

IV nicotine self-administration in rats using the consummatory operant licking response

Nicotine self-administered by tobacco smoking or chewing is very addictive in humans. Rat models have been developed in which nicotine is self-administered IV by the rats pressing a lever. However the reinforcing value of nicotine is much less in these models than the addictiveness of human tobacco use would indicate. The IV nicotine self-administration operant lever press model does not fully capture important aspects of tobacco use in humans. Conditioned oral consumption actions of smoking or chewing tobacco may play important roles in tobacco addiction. Neural circuitry underlying essential food consummatory responses may facilitate consummatory aspects of tobacco intake. To capture this motor consummatory aspect of tobacco addiction in the rat model of nicotine self-administration, we have developed a method of using a licking response instead of a lever press to self-administer IV nicotine. Sprague-Dawley rats were trained to lick one of two waterspouts for IV nicotine (0.03. mg/kg/infusion). With the licking response rats self-administered stable nicotine levels throughout 24 sessions (45. min each) of testing. The number of total licks/session significantly increased in a linear fashion over that period. The number of licks/infusion was substantial, rising steadily with training to an average of over 100 licks/infusion. Including the consummatory motor act with nicotine self-administration could help better model the compulsive aspects of tobacco addiction in humans. © 2010 Elsevier Inc.

Authors
Levin, ED; Hampton, D; Rose, JE
MLA Citation
Levin, ED, Hampton, D, and Rose, JE. "IV nicotine self-administration in rats using the consummatory operant licking response." Physiology and Behavior 101.5 (2010): 755-758.
PMID
20804779
Source
scival
Published In
Physiology & Behavior
Volume
101
Issue
5
Publish Date
2010
Start Page
755
End Page
758
DOI
10.1016/j.physbeh.2010.08.016

Introduction to the special issue on emerging high throughput and complementary model screens for neurotoxicology

Authors
Aschner, M; Crofton, KM; Levin, ED
MLA Citation
Aschner, M, Crofton, KM, and Levin, ED. "Introduction to the special issue on emerging high throughput and complementary model screens for neurotoxicology." Neurotoxicology and Teratology 32.1 (2010): 1-3.
PMID
19703556
Source
scival
Published In
Neurotoxicology and Teratology
Volume
32
Issue
1
Publish Date
2010
Start Page
1
End Page
3
DOI
10.1016/j.ntt.2009.08.006

Lasting Behavioral Consequences of Organophosphate Pesticide Exposure During Development

This chapter defines the vulnerability of the developing nervous system to organophosphate pesticides, in terms of cognitive functions, social and sex-related behavioral patterns, and body weight regulation. Impaired neurobehavioral development of children has been significantly linked in epidemiological studies with exposure to pesticides. Environmental epidemiological studies are essential for identifying toxic risks, but like any single scientific approach they have limitations. Determining the cause-and-effect relationship beyond significant association is a challenge. Significant behavioral alterations are reported after short-term, low-dose exposure to a variety of organophosphates during development. Because these effects were observed at doses that do not significantly inhibit acetylcholinesterase, other mechanisms in addition to inhibition of this important enzyme should be considered. The aim of toxicology is to be a predictive science, to prevent toxic damage. Animal model studies can work in concert with epidemiological research to resolve many of these issues. With regard to organophosphate (OP) pesticide-induced developmental neurobehavioral toxicity, laboratory animal model studies have clearly demonstrated that the developing nervous system is quite vulnerable to detrimental effects of OP pesticides, even if exposure was short-term and at doses that did not cause much inhibition of acetylcholinesterase. © 2010 Elsevier Inc. All rights reserved.

Authors
Timofeeva, OA; Levin, ED
MLA Citation
Timofeeva, OA, and Levin, ED. "Lasting Behavioral Consequences of Organophosphate Pesticide Exposure During Development." Hayes' Handbook of Pesticide Toxicology (2010): 837-846.
Source
scival
Published In
Hayes' Handbook of Pesticide Toxicology
Publish Date
2010
Start Page
837
End Page
846
DOI
10.1016/B978-0-12-374367-1.00033-1

Neonatal parathion exposure disrupts serotonin and dopamine synaptic function in rat brain regions: modulation by a high-fat diet in adulthood.

The consequences of exposure to developmental neurotoxicants are influenced by environmental factors. In the present study, we examined the role of dietary fat intake. We administered parathion to neonatal rats and then evaluated whether a high-fat diet begun in adulthood could modulate the persistent effects on 5HT and DA systems. Neonatal rats received parathion on postnatal days 1-4 at 0.1 or 0.2 mg/kg/day, straddling the cholinesterase inhibition threshold. In adulthood, half the animals in each exposure group were given a high-fat diet for 8 weeks. We assessed 5HT and DA concentrations and turnover in brain regions containing their respective cell bodies and projections. In addition, we monitored 5HT1A and 5HT2 receptor binding and the concentration of 5HT presynaptic transporters. Neonatal parathion exposure evoked widespread increases in neurotransmitter turnover, indicative of presynaptic hyperactivity, further augmented by 5HT receptor upregulation. In control rats, consumption of a high-fat diet recapitulated many of the changes seen with neonatal parathion exposure; the effects represented convergent mechanisms, since the high-fat diet often obtunded further increases caused by parathion. Neonatal parathion exposure causes lasting hyperactivity of 5HT and DA systems accompanied by 5HT receptor upregulation, consistent with "miswiring" of neuronal projections. A high-fat diet obtunds the effect of parathion, in part by eliciting similar changes itself. Thus, dietary factors may produce similar synaptic changes as do developmental neurotoxicants, potentially contributing to the increasing incidence of neurodevelopmental disorders.

Authors
Slotkin, TA; Wrench, N; Ryde, IT; Lassiter, TL; Levin, ED; Seidler, FJ
MLA Citation
Slotkin, TA, Wrench, N, Ryde, IT, Lassiter, TL, Levin, ED, and Seidler, FJ. "Neonatal parathion exposure disrupts serotonin and dopamine synaptic function in rat brain regions: modulation by a high-fat diet in adulthood." Neurotoxicol Teratol 31.6 (November 2009): 390-399.
PMID
19616088
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
31
Issue
6
Publish Date
2009
Start Page
390
End Page
399
DOI
10.1016/j.ntt.2009.07.003

Buspirone, chlordiazepoxide and diazepam effects in a zebrafish model of anxiety.

Zebrafish are becoming more widely used to study neurobehavioral pharmacology. We have developed a method to assess novel environment diving behavior of zebrafish as a model of stress response and anxiolytic drug effects. In a novel tank, zebrafish dwell in the bottom of the tank initially and then increase their swimming exploration to higher levels over time. We previously found that nicotine, which has anxiolytic effects in rodents and humans, significantly lessens the novel tank diving response in zebrafish. The specificity of the diving effect was validated with a novel vs. non-novel test tank. The novel tank diving response of zebrafish was tested when given three anxiolytic drugs from two different chemical and pharmacological classes: buspirone, chlordiazepoxide and diazepam. When the test tank was novel the diving response was clearly seen whereas it was significantly reduced when the test tank was not novel. Buspirone, a serotonergic (5HT(1A) receptor agonist) anxiolytic drug with some D(2) dopaminergic effect, had a pronounced anxiolytic-like effect in the zebrafish diving model at doses that did not have sedative effects. In contrast, chlordiazepoxide, a benzodiazepine anxiolytic drug, which is an effective agonist at GABA-A receptors, did not produce signs of anxiolysis in zebrafish over a broad dose range up to those that caused sedation. Diazepam another benzodiazepine anxiolytic drug did produce an anxiolytic effect at doses that did not cause sedation. The zebrafish novel tank diving task can be useful in discriminating anxiolytic drugs of several classes (serotonergic, benzodiazepines and nicotinic).

Authors
Bencan, Z; Sledge, D; Levin, ED
MLA Citation
Bencan, Z, Sledge, D, and Levin, ED. "Buspirone, chlordiazepoxide and diazepam effects in a zebrafish model of anxiety." Pharmacol Biochem Behav 94.1 (November 2009): 75-80.
PMID
19643124
Source
pubmed
Published In
Pharmacology, Biochemistry and Behavior
Volume
94
Issue
1
Publish Date
2009
Start Page
75
End Page
80
DOI
10.1016/j.pbb.2009.07.009

Nicotinic antagonist effects in the mediodorsal thalamic nucleus: regional heterogeneity of nicotinic receptor involvement in cognitive function.

Nicotine has been found in many studies to improve cognitive function. However, some studies have not found this effect and others have seen nicotine-induced impairments. Systemic administration bathes the brain with drugs. However, the brain is quite intricately organized with various regions playing very different roles in the bases of cognitive function. We have examined the role of nicotinic receptors in a variety of brain areas for memory. In the hippocampus and amygdala, local infusions of both alpha7 and alpha4beta2 antagonists methyllyaconitine (MLA) and dihydro-beta-erythroidine (DHbetaE) significantly impair memory. In the current studies we locally infused acute and chronic doses of MLA and DHbetaE into the mediodorsal thalamic nucleus and tested memory function on a 16-arm radial maze. The rats also received systemic nicotine to determine the impact of more generalized nicotine effects. Since nicotinic treatments are being developed for cognitive impairment of schizophrenia, interactions were studied with the antipsychotic drug clozapine. In the acute study, the 6.75 microg/side of DHbetaE improved working memory. Co-administration of MLA reversed the DHbetaE-induced improvement. Chronic DHbetaE infusions into the mediodorsal thalamic nucleus also improved working memory. Systemic nicotine reversed this effect. Clozapine had no significant interaction. Nicotinic alpha4beta2 receptors in the mediodorsal thalamic nucleus appear to play an opposite role with regard to working memory than those in the hippocampus and amygdala. Heterogeneity in response to nicotinic drugs given systemically may be due to anatomically distinct nicotinic systems in the brain and their unique roles in the neural bases of cognitive function.

Authors
Cannady, R; Weir, R; Wee, B; Gotschlich, E; Kolia, N; Lau, E; Brotherton, J; Levin, ED
MLA Citation
Cannady, R, Weir, R, Wee, B, Gotschlich, E, Kolia, N, Lau, E, Brotherton, J, and Levin, ED. "Nicotinic antagonist effects in the mediodorsal thalamic nucleus: regional heterogeneity of nicotinic receptor involvement in cognitive function." Biochem Pharmacol 78.7 (October 1, 2009): 788-794.
PMID
19477167
Source
pubmed
Published In
Biochemical Pharmacology
Volume
78
Issue
7
Publish Date
2009
Start Page
788
End Page
794
DOI
10.1016/j.bcp.2009.05.021

Genetic aspects of behavioral neurotoxicology.

Considerable progress has been made over the past couple of decades concerning the molecular bases of neurobehavioral function and dysfunction. The field of neurobehavioral genetics is becoming mature. Genetic factors contributing to neurologic diseases such as Alzheimer's disease have been found and evidence for genetic factors contributing to other diseases such as schizophrenia and autism are likely. This genetic approach can also benefit the field of behavioral neurotoxicology. It is clear that there is substantial heterogeneity of response with behavioral impairments resulting from neurotoxicants. Many factors contribute to differential sensitivity, but it is likely that genetic variability plays a prominent role. Important discoveries concerning genetics and behavioral neurotoxicity are being made on a broad front from work with invertebrate and piscine mutant models to classic mouse knockout models and human epidemiologic studies of polymorphisms. Discovering genetic factors of susceptibility to neurobehavioral toxicity not only helps identify those at special risk, it also advances our understanding of the mechanisms by which toxicants impair neurobehavioral function in the larger population. This symposium organized by Edward Levin and Annette Kirshner, brought together researchers from the laboratories of Michael Aschner, Douglas Ruden, Ulrike Heberlein, Edward Levin and Kathleen Welsh-Bohmer conducting studies with Caenorhabditis elegans, Drosophila, fish, rodents and humans studies to determine the role of genetic factors in susceptibility to behavioral impairment from neurotoxic exposure.

Authors
Levin, ED; Aschner, M; Heberlein, U; Ruden, D; Welsh-Bohmer, KA; Bartlett, S; Berger, K; Chen, L; Corl, AB; Eddins, D; French, R; Hayden, KM; Helmcke, K; Hirsch, HVB; Linney, E; Lnenicka, G; Page, GP; Possidente, D; Possidente, B; Kirshner, A
MLA Citation
Levin, ED, Aschner, M, Heberlein, U, Ruden, D, Welsh-Bohmer, KA, Bartlett, S, Berger, K, Chen, L, Corl, AB, Eddins, D, French, R, Hayden, KM, Helmcke, K, Hirsch, HVB, Linney, E, Lnenicka, G, Page, GP, Possidente, D, Possidente, B, and Kirshner, A. "Genetic aspects of behavioral neurotoxicology." Neurotoxicology 30.5 (September 2009): 741-753.
PMID
19647018
Source
pubmed
Published In
NeuroToxicology
Volume
30
Issue
5
Publish Date
2009
Start Page
741
End Page
753
DOI
10.1016/j.neuro.2009.07.014

Are adolescents more vulnerable to drug addiction than adults? Evidence from animal models.

BACKGROUND AND RATIONALE: Epidemiological evidence suggests that people who begin experimenting with drugs of abuse during early adolescence are more likely to develop substance use disorders (SUDs), but this correlation does not guarantee causation. Animal models, in which age of onset can be tightly controlled, offer a platform for testing causality. Many animal models address drug effects that might promote or discourage drug intake and drug-induced neuroplasticity. METHODS: We have reviewed the preclinical literature to investigate whether adolescent rodents are differentially sensitive to rewarding, reinforcing, aversive, locomotor, and withdrawal-induced effects of drugs of abuse. RESULTS AND CONCLUSIONS: The rodent model literature consistently suggests that the balance of rewarding and aversive effects of drugs of abuse is tipped toward reward in adolescence. However, increased reward does not consistently lead to increased voluntary intake: age effects on voluntary intake are drug and method specific. On the other hand, adolescents are consistently less sensitive to withdrawal effects, which could protect against compulsive drug seeking. Studies examining neuronal function have revealed several age-related effects but have yet to link these effects to vulnerability to SUDs. Taken together, the findings suggest factors which may promote recreational drug use in adolescents, but evidence relating to pathological drug-seeking behavior is lacking. A call is made for future studies to address this gap using behavioral models of pathological drug seeking and for neurobiologic studies to more directly link age effects to SUD vulnerability.

Authors
Schramm-Sapyta, NL; Walker, QD; Caster, JM; Levin, ED; Kuhn, CM
MLA Citation
Schramm-Sapyta, NL, Walker, QD, Caster, JM, Levin, ED, and Kuhn, CM. "Are adolescents more vulnerable to drug addiction than adults? Evidence from animal models." Psychopharmacology (Berl) 206.1 (September 2009): 1-21. (Review)
PMID
19547960
Source
pubmed
Published In
Psychopharmacology
Volume
206
Issue
1
Publish Date
2009
Start Page
1
End Page
21
DOI
10.1007/s00213-009-1585-5

The toxicology of climate change: environmental contaminants in a warming world.

Climate change induced by anthropogenic warming of the earth's atmosphere is a daunting problem. This review examines one of the consequences of climate change that has only recently attracted attention: namely, the effects of climate change on the environmental distribution and toxicity of chemical pollutants. A review was undertaken of the scientific literature (original research articles, reviews, government and intergovernmental reports) focusing on the interactions of toxicants with the environmental parameters, temperature, precipitation, and salinity, as altered by climate change. Three broad classes of chemical toxicants of global significance were the focus: air pollutants, persistent organic pollutants (POPs), including some organochlorine pesticides, and other classes of pesticides. Generally, increases in temperature will enhance the toxicity of contaminants and increase concentrations of tropospheric ozone regionally, but will also likely increase rates of chemical degradation. While further research is needed, climate change coupled with air pollutant exposures may have potentially serious adverse consequences for human health in urban and polluted regions. Climate change producing alterations in: food webs, lipid dynamics, ice and snow melt, and organic carbon cycling could result in increased POP levels in water, soil, and biota. There is also compelling evidence that increasing temperatures could be deleterious to pollutant-exposed wildlife. For example, elevated water temperatures may alter the biotransformation of contaminants to more bioactive metabolites and impair homeostasis. The complex interactions between climate change and pollutants may be particularly problematic for species living at the edge of their physiological tolerance range where acclimation capacity may be limited. In addition to temperature increases, regional precipitation patterns are projected to be altered with climate change. Regions subject to decreases in precipitation may experience enhanced volatilization of POPs and pesticides to the atmosphere. Reduced precipitation will also increase air pollution in urbanized regions resulting in negative health effects, which may be exacerbated by temperature increases. Regions subject to increased precipitation will have lower levels of air pollution, but will likely experience enhanced surface deposition of airborne POPs and increased run-off of pesticides. Moreover, increases in the intensity and frequency of storm events linked to climate change could lead to more severe episodes of chemical contamination of water bodies and surrounding watersheds. Changes in salinity may affect aquatic organisms as an independent stressor as well as by altering the bioavailability and in some instances increasing the toxicity of chemicals. A paramount issue will be to identify species and populations especially vulnerable to climate-pollutant interactions, in the context of the many other physical, chemical, and biological stressors that will be altered with climate change. Moreover, it will be important to predict tipping points that might trigger or accelerate synergistic interactions between climate change and contaminant exposures.

Authors
Noyes, PD; McElwee, MK; Miller, HD; Clark, BW; Van Tiem, LA; Walcott, KC; Erwin, KN; Levin, ED
MLA Citation
Noyes, PD, McElwee, MK, Miller, HD, Clark, BW, Van Tiem, LA, Walcott, KC, Erwin, KN, and Levin, ED. "The toxicology of climate change: environmental contaminants in a warming world." Environ Int 35.6 (August 2009): 971-986. (Review)
Website
http://hdl.handle.net/10161/6983
PMID
19375165
Source
pubmed
Published In
Environment International
Volume
35
Issue
6
Publish Date
2009
Start Page
971
End Page
986
DOI
10.1016/j.envint.2009.02.006

Carisbamate, a novel antiepileptic candidate compound, attenuates alcohol intake in alcohol-preferring rats.

BACKGROUND: Since 1994, when naltrexone (Revia) was approved by the FDA for the treatment of alcoholism, only 2 other drugs (Campral and Topamax have been approved for alcoholism treatment. However, various experimental drugs, including antiepileptic medications, have been tested in both animal models and in humans with some promising results. The purpose of this project was to study the effect of the novel neuromodulator carisbamate, which is in development for epilepsy treatment, on alcohol intake in selectively bred alcohol-preferring rats. METHODS: Male alcohol-preferring inbred P rats were allowed to freely drink water or alcohol (10%, v/v) using a 2-bottle choice procedure. After stable baselines for alcohol and water intakes were established, the acute effects of oral carisbamate (0, 10, 30, 45, 60, and 90 mg/kg) were assessed. Then, the chronic effect of the compound (60 mg/kg/day for 14 consecutive days) on alcohol intake was assessed in a separate group of male P rats. In another set of experiments, the effects of carisbamate and naltrexone on alcohol withdrawal-induced elevated drinking of alcohol, an index of craving, were compared. Rats were withdrawn from alcohol for 24 hours and were given vehicle, 20 mg/kg naltrexone or 60 mg/kg carisbamate 30 minutes before re-exposure to alcohol. Alcohol and water intake was measured 6 hours after alcohol re-exposure. To determine the effects of carisbamate on saccharin preference, rats were put on a 2-bottle choice of water versus a solution of 2% saccharin. Then, the effect of the highest dose of carisbamate (90 mg/kg) and naltrexone (20 mg/kg) and the vehicle on saccharin preference was determined. RESULTS: Our results showed that there was a selective dose-dependent reduction in alcohol intake and preference in the alcohol-preferring P rat after an acute oral administration of carisbamate. There were no significant effects on food or water intake. Chronic administration of carisbamate significantly reduced alcohol intake and preference initially, but partial tolerance developed after the 10th treatment. The degree of tolerance development was less than that observed for naltrexone. Acute administration of carisbamate was more effective than naltrexone in reducing enhanced alcohol intake after a period of alcohol deprivation. Compared with control vehicle neither carisbamate nor naltrexone had a significant effect on saccharin intake and preference. CONCLUSION: The novel neuromodulator compound carisbamate has a favorable profile of effects on alcohol intake and related measures and should be considered for testing on human alcoholics.

Authors
Rezvani, AH; Overstreet, DH; Vaidya, AH; Zhao, B; Levin, ED
MLA Citation
Rezvani, AH, Overstreet, DH, Vaidya, AH, Zhao, B, and Levin, ED. "Carisbamate, a novel antiepileptic candidate compound, attenuates alcohol intake in alcohol-preferring rats." Alcohol Clin Exp Res 33.8 (August 2009): 1366-1373.
PMID
19413647
Source
pubmed
Published In
Alcoholism: Clinical and Experimental Research
Volume
33
Issue
8
Publish Date
2009
Start Page
1366
End Page
1373
DOI
10.1111/j.1530-0277.2009.00966.x

Consumption of a high-fat diet in adulthood ameliorates the effects of neonatal parathion exposure on acetylcholine systems in rat brain regions.

BACKGROUND: Developmental exposure to a wide variety of developmental neurotoxicants, including organophosphate pesticides, evokes late-emerging and persistent abnormalities in acetylcholine (ACh) systems. We are seeking interventions that can ameliorate or reverse the effects later in life. OBJECTIVES: We administered parathion to neonatal rats and then evaluated whether a high-fat diet begun in adulthood could reverse the effects on ACh systems. METHODS: Neonatal rats received parathion on postnatal days 1-4 at 0.1 or 0.2 mg/kg/day, straddling the cholinesterase inhibition threshold. In adulthood, half the animals were switched to a high-fat diet for 8 weeks. We assessed three indices of ACh synaptic function: nicotinic ACh receptor binding, choline acetyltransferase activity, and hemicholinium-3 binding. Determinations were performed in brain regions comprising all the major ACh projections and cell bodies. RESULTS: Neonatal parathion exposure evoked widespread abnormalities in ACh synaptic markers, encompassing effects in brain regions possessing ACh projections and ACh cell bodies. In general, males were affected more than females. Of 17 regional ACh marker abnormalities (10 male, 7 female), 15 were reversed by the high-fat diet. CONCLUSIONS: A high-fat diet reverses neurodevelopmental effects of neonatal parathion exposure on ACh systems. This points to the potential for nonpharmacologic interventions to offset the effects of developmental neurotoxicants. Further, cryptic neurodevelopmental deficits evoked by environmental exposures may thus engender a later preference for a high-fat diet to maintain normal ACh function, ultimately contributing to obesity.

Authors
Slotkin, TA; Lassiter, TL; Ryde, IT; Wrench, N; Levin, ED; Seidler, FJ
MLA Citation
Slotkin, TA, Lassiter, TL, Ryde, IT, Wrench, N, Levin, ED, and Seidler, FJ. "Consumption of a high-fat diet in adulthood ameliorates the effects of neonatal parathion exposure on acetylcholine systems in rat brain regions." Environ Health Perspect 117.6 (June 2009): 916-922.
PMID
19590683
Source
pubmed
Published In
Environmental health perspectives
Volume
117
Issue
6
Publish Date
2009
Start Page
916
End Page
922
DOI
10.1289/ehp.0800459

Hippocampal infusions of apolipoprotein E peptides induce long-lasting cognitive impairment.

The inheritance of the varepsilon4 allele of apolipoprotein E (ApoE4) and cholinergic system dysfunction have long been associated with the pathology of Alzheimer's disease (AD). Recently, in vitro studies have established a direct link between ApoE and cholinergic function in that synthetic peptides containing segments of the ApoE protein (ApoE(133-149) and ApoE(141-148)) interact with alpha7 nicotinic acetylcholine receptors (nAChRs) in the hippocampus. This raises the possibility that ApoE peptides may contribute to cognitive impairment in AD in that the hippocampus plays a key role in cognitive functioning. To test this, we acutely infused ApoE peptides into the ventral hippocampus of female Sprague-Dawley rats and assessed the resultant effects on radial-arm maze choice accuracy over a period of weeks after the infusion. Local ventral hippocampal infusion of ApoE peptides caused significant cognitive impairment in radial-arm maze learning that persisted several weeks after the acute infusion. This persisting deficit may be an important model for understanding the relationship between ApoE protein-induced neurotoxicity and cognitive impairment as well as serve as a platform for the development of new therapies to avoid neurotoxicity and cognitive decline.

Authors
Eddins, D; Klein, RC; Yakel, JL; Levin, ED
MLA Citation
Eddins, D, Klein, RC, Yakel, JL, and Levin, ED. "Hippocampal infusions of apolipoprotein E peptides induce long-lasting cognitive impairment." Brain Res Bull 79.2 (April 29, 2009): 111-115.
PMID
19185602
Source
pubmed
Published In
Brain Research Bulletin
Volume
79
Issue
2
Publish Date
2009
Start Page
111
End Page
115
DOI
10.1016/j.brainresbull.2009.01.003

Chronic underactivity of medial frontal cortical beta2-containing nicotinic receptors increases clozapine-induced working memory impairment in female rats.

Nicotinic receptor decreases in the frontal cortex and hippocampus are important mediators of cognitive impairment in both schizophrenia and Alzheimer's disease. Drug treatments for these diseases should take into account the impacts of compromised brain function on drug response. This study investigated the impact of compromised nicotinic receptor activity in the frontal cortex in rats on memory function. Since both Alzheimer's disease and schizophrenia can involve psychosis, antipsychotic drugs are often given. The impacts of antipsychotic drugs on cognitive function have been found to be quite variable. It is the hypothesis of this and previous studies that the cognitive effects of antispychotic drugs on cognitive function depend on the integrity of brain systems involved in cognition. Previously in studies of the hippocampus, we found that chronic inhibition of beta2-containing nicotinic receptors with dihydro-beta-erythrodine (DHbetaE) impaired working memory and that this effect was attenuated by the antipsychotic drug clozapine. In contrast, chronic hippocampal alpha7 nicotinic receptor blockade with methyllycaconitine (MLA) potentiated the clozapine-induced memory impairment which is seen in rats without compromised nicotinic receptor activity. The current study determined medial frontal cortical alpha7 and beta2-containing nicotinic receptor involvement in memory and the interactions with antipsychotic drug therapy with clozapine. Chronic DHbetaE and MLA infusion effects and interactions with systemic clozapine were assessed in female rats tested for memory on the radial-arm maze. Antipsychotic drug interactions with chronic systemic nicotine were investigated because nicotinic procognitive treatment has been proposed. The same local infusion DHbetaE dose that impaired memory with hippocampal infusion did not impair memory when infused in the medial frontal cortex. Frontal DHbetaE infusion potentiated clozapine-induced memory impairment, whereas previously the memory impairment caused by hippocampal DHbetaE infusion was attenuated by clozapine. Frontal cortical MLA infusions at a dose that previously was found to potentiate the clozapine-induced memory impairment with hippocampal infusion had no significant effect when infused into the medial frontal cortex. The location and subtype of nicotinic receptor underactivity are critical determinates for clozapine effects on memory. Patients with hippocampal beta2-containing nicotinic receptor loss may be well treated with clozapine therapy, while those with frontal cortical beta2-containing receptor loss may have a potentiated memory impairment caused by clozapine.

Authors
Levin, ED; Perkins, A; Brotherton, T; Qazi, M; Berez, C; Montalvo-Ortiz, J; Davis, K; Williams, P; Christopher, NC
MLA Citation
Levin, ED, Perkins, A, Brotherton, T, Qazi, M, Berez, C, Montalvo-Ortiz, J, Davis, K, Williams, P, and Christopher, NC. "Chronic underactivity of medial frontal cortical beta2-containing nicotinic receptors increases clozapine-induced working memory impairment in female rats." Prog Neuropsychopharmacol Biol Psychiatry 33.2 (March 17, 2009): 296-302.
PMID
19146909
Source
pubmed
Published In
Progress in Neuro-Psychopharmacology & Biological Psychiatry
Volume
33
Issue
2
Publish Date
2009
Start Page
296
End Page
302
DOI
10.1016/j.pnpbp.2008.12.003

Effect of R3487/MEM3454, a novel nicotinic alpha7 receptor partial agonist and 5-HT3 antagonist on sustained attention in rats.

It is well established that nicotinic systems in the brain are critically involved in attentional processes in both animals and humans. The current study assessed the effects of a novel nicotinic alpha7 receptor partial agonist and 5-HT3 antagonist, R3487/MEM3454 (also referred to as R3487 or MEM 3454) on sustained attention in rats performing an operant visual signal detection task. The effects of R3487/MEM3454 were compared to those of the acetylcholinesterase inhibitor/nicotinic alpha7 allosteric positive modulator galanthamine. Adult female Sprague-Dawley rats were injected subcutaneously with R3487/MEM3454 (0.03, 0.1, 0.15, 0.3 and 0.6 mg/kg), galanthamine (0.25, 0.5, 1, 2 mg/kg) or vehicle 30 min before the attentional test. In the second study, the time-dependent effects of R3487/MEM3454 were assessed by injecting the compound (0.6 mg/kg, s.c.) at different pretreatment intervals (30, 60 or 90 min) before the start of the attentional task. Our results show a significant dose-effect for R3487/MEM3454 on percent hit accuracy performance without any significant alteration on percent correct rejection performance. In the time-dependent test, R3487/MEM3454 significantly increased the percent hit accuracy performance when animals were injected 60 min before the start of the attentional task. Administration of galanthamine failed to significantly increase percent hit accuracy performance and increasing the dose of galanthamine produced a decrease in percent correct rejection performance. The present findings with R3487/MEM3454 suggest that nicotinic alpha7 receptors and/or 5-HT3 receptors may play an important role in modulating sustained attention and that R3487/MEM3454 may have therapeutic potential in improving sustained attention in humans.

Authors
Rezvani, AH; Kholdebarin, E; Brucato, FH; Callahan, PM; Lowe, DA; Levin, ED
MLA Citation
Rezvani, AH, Kholdebarin, E, Brucato, FH, Callahan, PM, Lowe, DA, and Levin, ED. "Effect of R3487/MEM3454, a novel nicotinic alpha7 receptor partial agonist and 5-HT3 antagonist on sustained attention in rats." Prog Neuropsychopharmacol Biol Psychiatry 33.2 (March 17, 2009): 269-275.
PMID
19110025
Source
pubmed
Published In
Progress in Neuro-Psychopharmacology & Biological Psychiatry
Volume
33
Issue
2
Publish Date
2009
Start Page
269
End Page
275
DOI
10.1016/j.pnpbp.2008.11.018

Attenuation of pharmacologically-induced attentional impairment by methylphenidate in rats.

Methylphenidate is widely used as a treatment option for attention deficit hyperactivity disorder. In animal models of attentional impairment, it is an important validation to determine whether this clinically effective treatment attenuates deficits. The purpose of the current study was to determine whether methylphenidate can diminish attentional impairment induced by three pharmacological agents with different mechanisms of action: scopolamine, mecamylamine, and dizocilpine. Female rats were trained on an operant visual signal detection task. Ten min before the test, the rats were injected subcutaneously with methylphenidate (0, 0.1, 0.3 mg/kg), scopolamine (0, 0.005, 0.01 mg/kg), mecamylamine (0, 2, 4 mg/kg), dizocilpine (0, 0.025, 0.05 mg/kg) or combinations of methylphenidate with these drugs. In each of the experiments, all rats received every treatment in a repeated measures counterbalanced order. Correction rejection accuracy was impaired by all three of the antagonists and these effects were attenuated by methylphenidate. Both scopolamine at 0.01 and dizocilpine at 0.05 mg/kg significantly impaired percent correct rejection choice accuracy, an effect that was ameliorated by methylphenidate. Mecamylamine (4 mg/kg) impaired attentional performance by reducing percent hit and percent correct rejection. Co-administration of methylphenidate failed to significantly affect the mecamylamine-induced attentional impairment. Methylphenidate alone at 0.3 mg/kg significantly improved percent hit choice accuracy only in low-performing rats in one experiment, an effect which was reversed by scopolamine. These data show that methylphenidate effectively reverses the attentional impairment caused by scopolamine and dizocilpine. These findings further validate the operant visual signal detection task for assessing attentional impairments and their reversal.

Authors
Rezvani, AH; Kholdebarin, E; Cauley, MC; Dawson, E; Levin, ED
MLA Citation
Rezvani, AH, Kholdebarin, E, Cauley, MC, Dawson, E, and Levin, ED. "Attenuation of pharmacologically-induced attentional impairment by methylphenidate in rats." Pharmacol Biochem Behav 92.1 (March 2009): 141-146.
PMID
19041337
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
92
Issue
1
Publish Date
2009
Start Page
141
End Page
146
DOI
10.1016/j.pbb.2008.11.005

Attenuation of auditory startle and prepulse inhibition by unexpected changes in ambient illumination through dopaminergic mechanisms.

We investigated the role of dopaminergic mechanisms in the attenuation of the acoustic startle response and prepulse inhibition (PPI) in rats by the introduction of unexpected changes in environment illumination. Experiment 1 showed that Dark-to-Light transitions robustly reduce startle responses and PPI. Experiment 2 showed that this phenomenon habituates across repeated testing sessions and reappears after an interval without testing. Experiment 3 demonstrated that haloperidol blocks the startle and PPI-reducing effect of the Dark-to-Light transition. We show how a computational model of acoustic startle response and prepulse inhibition can be extended to incorporate the empirical effects demonstrated in this study. We conclude that sensory gating as measured by prepulse inhibition is markedly attenuated in situations where novel stimuli are introduced during a test session and that dopaminergic systems may be involved in the dynamic changes evoked by the onset of illumination.

Authors
Schmajuk, NA; Larrauri, JA; De la Casa, LG; Levin, ED
MLA Citation
Schmajuk, NA, Larrauri, JA, De la Casa, LG, and Levin, ED. "Attenuation of auditory startle and prepulse inhibition by unexpected changes in ambient illumination through dopaminergic mechanisms." Behav Brain Res 197.2 (February 11, 2009): 251-261.
PMID
18801390
Source
pubmed
Published In
Behavioural Brain Research
Volume
197
Issue
2
Publish Date
2009
Start Page
251
End Page
261
DOI
10.1016/j.bbr.2008.08.030

Nicotinic alpha7- or beta2-containing receptor knockout: effects on radial-arm maze learning and long-term nicotine consumption in mice.

Classically, it has been thought that high-affinity nicotinic receptors-containing beta2 subunits are the most important receptor subtypes for nicotinic involvement in cognitive function and nicotine self-administration, while low affinity alpha7-containing nicotinic receptors have not been thought to be important. In the current study, we found that knockout of either beta2 or alpha7 subunits caused significant deficits in spatial discrimination in mice. The character of the impairment in the two knockouts was different. The beta2 knockout preferentially impaired cognition in males while the alpha7 caused impairment regardless of sex. Both beta2- and alpha7-containing nicotinic receptors also are important for nicotine self-administration, also in different ways. Most animal model studies of nicotine self-administration are relatively short-term whereas the problem of tobacco addiction is considerably longer-term. To better model the impact of nicotinic receptor subtypes on nicotine self-administration over the long-term, we studied the impact of genetic knockout of low affinity alpha7 receptors vs. high-affinity beta2-containing nicotinic receptors. Mice with knockouts of either of these receptors and their wildtype counter parts were given free access to a choice of nicotine-containing and nicotine-free solution in their home cages on a continuous basis over a period of 5 months. During the first few weeks, the beta2-containing nicotinic receptor knockout mice showed a significant decrease in nicotine consumption relative to wildtype mice, whereas the alpha7 knockout mice did not significantly differ from wildtype controls at the beginning of their access to nicotine. Interestingly, in the longer-term after the first few weeks of nicotine access, the beta2 knockout mice returned to wildtype mouse levels of nicotine consumption, whereas the alpha7 knockout mice developed an emergent decrease in nicotine consumption. The alpha7 receptor knockout-induced decrease in nicotine consumption persisted for the 5-month period of the study. Both alpha7- and beta2-containing nicotinic receptors play critical roles in cognitive function and nicotine self-administration. Regarding cognitive function, beta2-containing receptors are important for maintaining normal sex differences in spatial learning and memory, whereas alpha7 receptors are important for cognitive function regardless of sex. Regarding nicotine self-administration high-affinity beta2-containing nicotinic receptors are important for consumption during the initial phase of nicotine access, but it is the alpha7 nicotinic receptors that are important for the longer-term regulation of nicotine consumption.

Authors
Levin, ED; Petro, A; Rezvani, AH; Pollard, N; Christopher, NC; Strauss, M; Avery, J; Nicholson, J; Rose, JE
MLA Citation
Levin, ED, Petro, A, Rezvani, AH, Pollard, N, Christopher, NC, Strauss, M, Avery, J, Nicholson, J, and Rose, JE. "Nicotinic alpha7- or beta2-containing receptor knockout: effects on radial-arm maze learning and long-term nicotine consumption in mice." Behav Brain Res 196.2 (January 23, 2009): 207-213.
PMID
18831991
Source
pubmed
Published In
Behavioural Brain Research
Volume
196
Issue
2
Publish Date
2009
Start Page
207
End Page
213
DOI
10.1016/j.bbr.2008.08.048

Developmental neurotoxicity of parathion: progressive effects on serotonergic systems in adolescence and adulthood.

Neonatal exposures to organophosphates that are not acutely symptomatic or that produce little or no cholinesterase inhibition can nevertheless compromise the development and later function of critical neural pathways, including serotonin (5HT) systems that regulate emotional behaviors. We administered parathion to newborn rats on postnatal days (PN) 1-4 at doses spanning the threshold for detectable cholinesterase inhibition (0.1 mg/kg/day) and the first signs of loss of viability (0.2 mg/kg/day). In adolescence (PN30), young adulthood (PN60) and full adulthood (PN100), we measured radioligand binding to 5HT(1A) and 5HT(2) receptors, and to the 5HT transporter in the brain regions comprising all the major 5HT projections and 5HT cell bodies. Parathion caused a biphasic effect over later development with initial, widespread upregulation of 5HT(1A) receptors that peaked in the frontal/parietal cortex by PN60, followed by a diminution of that effect in most regions and emergence of deficits at PN100. There were smaller, but statistically significant changes in 5HT(2) receptors and the 5HT transporter. These findings stand in strong contrast to previous results with neonatal exposure to a different organophosphate, chlorpyrifos, which evoked parallel upregulation of all three 5HT synaptic proteins that persisted from adolescence through full adulthood and that targeted males much more than females. Our results support the view that the various organophosphates have disparate effects on 5HT systems, distinct from their shared property as cholinesterase inhibitors, and the targeting of 5HT function points toward the importance of studying the impact of these agents on 5HT-linked behaviors.

Authors
Slotkin, TA; Levin, ED; Seidler, FJ
MLA Citation
Slotkin, TA, Levin, ED, and Seidler, FJ. "Developmental neurotoxicity of parathion: progressive effects on serotonergic systems in adolescence and adulthood." Neurotoxicol Teratol 31.1 (January 2009): 11-17.
PMID
18773955
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
31
Issue
1
Publish Date
2009
Start Page
11
End Page
17
DOI
10.1016/j.ntt.2008.08.004

Nicotine effects on learning in zebrafish: the role of dopaminergic systems.

RATIONALE: Nicotine improves cognitive function in a number of animal models including rats, mice, monkeys, and recently, zebrafish. The zebrafish model allows higher throughput and ease in discovering mechanisms of cognitive improvement. MATERIALS AND METHODS: To further characterize the neural bases of nicotine effects on learning in zebrafish, we determined changes in dopaminergic systems that accompany nicotine-enhanced learning. RESULTS: Nicotine improved learning and increased brain levels of dihydroxyphenylacetic acid (DOPAC), the primary dopamine metabolite. There was a significant correlation between choice accuracy and DOPAC levels. The nicotinic antagonist mecamylamine blocked the nicotine-induced increase in DOPAC concentrations, in line with our previous finding that mecamylamine reversed nicotine-induced learning improvement. CONCLUSIONS: Dopamine systems are related to learning in zebrafish; nicotine exposure increases both learning rates and DOPAC levels; and nicotinic antagonist administration blocks nicotine-induced rises in DOPAC concentrations. Rapid cognitive assessment of drugs with zebrafish could serve as a useful screening tool for the development of new therapeutics for cognitive dysfunction.

Authors
Eddins, D; Petro, A; Williams, P; Cerutti, DT; Levin, ED
MLA Citation
Eddins, D, Petro, A, Williams, P, Cerutti, DT, and Levin, ED. "Nicotine effects on learning in zebrafish: the role of dopaminergic systems." Psychopharmacology (Berl) 202.1-3 (January 2009): 103-109.
PMID
18716760
Source
pubmed
Published In
Psychopharmacology
Volume
202
Issue
1-3
Publish Date
2009
Start Page
103
End Page
109
DOI
10.1007/s00213-008-1287-4

Persistent behavioral alterations in rats neonatally exposed to low doses of the organophosphate pesticide, parathion.

Although developmental exposures of rats to low levels of the organophosphate pesticides (OPs), chlorpyrifos (CPF) or diazinon (DZN), both cause persistent neurobehavioral effects, there are important differences in their neurotoxicity. The current study extended investigation to parathion (PTN), an OP that has higher systemic toxicity than either CPF or DZN. We gave PTN on postnatal days (PND) 1-4 at doses spanning the threshold for systemic toxicity (0, 0.1 or 0.2 mg/kg/day, s.c.) and performed a battery of emotional and cognitive behavioral tests in adolescence through adulthood. The higher PTN dose increased time spent on the open arms and the number of center crossings in the plus maze, indicating greater risk-taking and overall activity. This group also showed a decrease in tactile startle response without altering prepulse inhibition, indicating a blunted acute sensorimotor reaction without alteration in sensorimotor plasticity. T-maze spontaneous alternation, novelty-suppressed feeding, preference for sweetened chocolate milk, and locomotor activity were not significantly affected by neonatal PTN exposure. During radial-arm maze acquisition, rats given the lower PTN dose committed fewer errors compared to controls and displayed lower sensitivity to the amnestic effects of the NMDA receptor blocker, dizocilpine. No PTN effects were observed with regard to the sensitivity to blockade of muscarinic and nicotinic cholinergic receptors, or serotonin 5HT(2) receptors. This study shows that neonatal PTN exposure evokes long-term changes in behavior, but the effects are less severe, and in some incidences opposite in nature, to those seen earlier for CPF or DZN, findings consistent with our neurochemical studies showing different patterns of effects and less neurotoxic damage with PTN. Our results reinforce the conclusion that low dose exposure to different OPs can have quite different neurotoxic effects, obviously unconnected to their shared property as cholinesterase inhibitors.

Authors
Timofeeva, OA; Sanders, D; Seemann, K; Yang, L; Hermanson, D; Regenbogen, S; Agoos, S; Kallepalli, A; Rastogi, A; Braddy, D; Wells, C; Perraut, C; Seidler, FJ; Slotkin, TA; Levin, ED
MLA Citation
Timofeeva, OA, Sanders, D, Seemann, K, Yang, L, Hermanson, D, Regenbogen, S, Agoos, S, Kallepalli, A, Rastogi, A, Braddy, D, Wells, C, Perraut, C, Seidler, FJ, Slotkin, TA, and Levin, ED. "Persistent behavioral alterations in rats neonatally exposed to low doses of the organophosphate pesticide, parathion." Brain Res Bull 77.6 (December 16, 2008): 404-411.
PMID
18817854
Source
pubmed
Published In
Brain Research Bulletin
Volume
77
Issue
6
Publish Date
2008
Start Page
404
End Page
411
DOI
10.1016/j.brainresbull.2008.08.019

Ketanserin, a 5-HT2 receptor antagonist, decreases nicotine self-administration in rats.

Nicotine intake constitutes a principal mechanism for tobacco addiction. In addition to primary effects on nicotinic acetylcholine receptors, nicotine has cascading effects, which may also underlie its neurobehavioral actions. Nicotine induces serotonin (5-HT) release, which has not classically been thought to be involved in tobacco addiction as dopamine has. However, addiction can be characterized more as a disorder of compulsion than a disorder of enjoyment. 5-HT mechanisms play key roles in compulsive disorders. Nicotine-induced 5-HT release may be a key to tobacco addiction. Ketanserin, a 5-HT2a and 5-HT2c receptor antagonist, significantly attenuates nicotine effects on attention and memory. These studies were conducted to determine if ketanserin would reduce nicotine self-administration in rats. Male Sprague-Dawley rats (N=12) were given initial food pellet training and then 10 sessions of nicotine self-administration training (0.03 mg/kg/infusion, i.v.). Then the rats were administered ketanserin (1 or 2 mg/kg, s.c.) or the saline vehicle. Ketanserin (2 mg/kg) significantly decreased nicotine self-administration. This did not seem to be due to sedative or amnestic effects of ketanserin. In a second study, the effects of repeated administration of 2 mg/kg ketanserin (N=11) vs. saline injections (N=10) were examined. In the initial phase, the acute effectiveness of ketanserin in significantly reducing nicotine self-administration was replicated. The effect became attenuated during the following several sessions, but the significant effect became re-established during the final phases of this two-week study. 5-HT mechanisms play critical roles in the maintenance of nicotine self-administration. Better understanding of those roles may help lead to new 5-HT-based treatments for tobacco addiction.

Authors
Levin, ED; Slade, S; Johnson, M; Petro, A; Horton, K; Williams, P; Rezvani, AH; Rose, JE
MLA Citation
Levin, ED, Slade, S, Johnson, M, Petro, A, Horton, K, Williams, P, Rezvani, AH, and Rose, JE. "Ketanserin, a 5-HT2 receptor antagonist, decreases nicotine self-administration in rats." Eur J Pharmacol 600.1-3 (December 14, 2008): 93-97.
PMID
18950618
Source
pubmed
Published In
European Journal of Pharmacology
Volume
600
Issue
1-3
Publish Date
2008
Start Page
93
End Page
97
DOI
10.1016/j.ejphar.2008.10.016

Exposure of neonatal rats to parathion elicits sex-selective reprogramming of metabolism and alters the response to a high-fat diet in adulthood.

BACKGROUND: Developmental exposures to organophosphate pesticides are virtually ubiquitous. These agents are neurotoxicants, but recent evidence also points to lasting effects on metabolism. OBJECTIVES: We administered parathion to neonatal rats. In adulthood, we assessed the impact on weight gain, food consumption, and glucose and lipid homeostasis, as well as the interaction with the effects of a high-fat diet. METHODS: Neonatal rats were given parathion on postnatal days 1-4 using doses (0.1 or 0.2 mg/kg/day) that straddle the threshold for barely detectable cholinesterase inhibition and the first signs of systemic toxicity. In adulthood, animals were either maintained on standard lab chow or switched to a high-fat diet for 7 weeks. RESULTS: In male rats on a normal diet, the low-dose parathion exposure caused increased weight gain but also evoked signs of a prediabetic state, with elevated fasting serum glucose and impaired fat metabolism. The higher dose of parathion reversed the weight gain and caused further metabolic defects. Females showed greater sensitivity to metabolic disruption, with weight loss at either parathion dose, and greater imbalances in glucose and lipid metabolism. At 0.1 mg/kg/day parathion, females showed enhanced weight gain on the high-fat diet; This effect was reversed in the 0.2-mg/kg/day parathion group, and was accompanied by even greater deficits in glucose and fat metabolism. CONCLUSIONS: Neonatal low-dose parathion exposure disrupts glucose and fat homeostasis in a persistent and sex-selective manner. Early-life toxicant exposure to organophosphates or other environmental chemicals may play a role in the increased incidence of obesity and diabetes.

Authors
Lassiter, TL; Ryde, IT; Mackillop, EA; Brown, KK; Levin, ED; Seidler, FJ; Slotkin, TA
MLA Citation
Lassiter, TL, Ryde, IT, Mackillop, EA, Brown, KK, Levin, ED, Seidler, FJ, and Slotkin, TA. "Exposure of neonatal rats to parathion elicits sex-selective reprogramming of metabolism and alters the response to a high-fat diet in adulthood." Environ Health Perspect 116.11 (November 2008): 1456-1462.
PMID
19057696
Source
pubmed
Published In
Environmental health perspectives
Volume
116
Issue
11
Publish Date
2008
Start Page
1456
End Page
1462
DOI
10.1289/ehp.11673

The role of alpha7 and alpha4beta2 nicotinic receptors in the nicotine-induced anxiolytic effect in zebrafish.

Zebrafish (Danio rerio) have been widely used to study the molecular mechanisms of development including neurodevelopment. More recently, they have begun to be used to study neuropharmacology and neurotoxicology. Critical for this line of research are methods to study behavioral function in zebrafish. Previous studies have compared zebrafish with mammalian models to determine similarities and differences in locomotor behavior, learning and memory. Relatively little research has been conducted on stress response and anxiety behavior as well as the pharmacologic response in zebrafish. We have developed a test for zebrafish to assess stress response and anxiety: the novel tank diving test. In this short test normally zebrafish dive to the bottom of a novel tank and then gradually over the 5-min test begin exploring higher levels of the tank. Nicotine, which has anxiolytic effects in rodents and humans was found to diminish this novel tank diving response in zebrafish. The current study examined the nicotinic receptor subtype selectivity involved in the actions of nicotine. Two nicotinic receptor subtype selective antagonists were used: MLA (an alpha7 antagonist) and DHbetaE (an alpha4beta2 antagonist). We replicated our previous finding of the anxiolytic effect of nicotine with significantly less bottom dwelling by the fish after nicotine treatment. This nicotine-induced anxiolytic effect was reversed by both MLA and DHbetaE, indicating that both nicotinic alpha7 and alpha4beta2 receptors are involved in the nicotinic effect on anxiety in zebrafish.

Authors
Bencan, Z; Levin, ED
MLA Citation
Bencan, Z, and Levin, ED. "The role of alpha7 and alpha4beta2 nicotinic receptors in the nicotine-induced anxiolytic effect in zebrafish." Physiol Behav 95.3 (October 20, 2008): 408-412.
PMID
18671990
Source
pubmed
Published In
Physiology & Behavior
Volume
95
Issue
3
Publish Date
2008
Start Page
408
End Page
412
DOI
10.1016/j.physbeh.2008.07.009

Exposure of neonatal rats to parathion elicits sex-selective impairment of acetylcholine systems in brain regions during adolescence and adulthood.

BACKGROUND: Organophosphates elicit developmental neurotoxicity through multiple mechanisms other than their shared property as cholinesterase inhibitors. Accordingly, these agents may differ in their effects on specific brain circuits. OBJECTIVES: We gave parathion to neonatal rats [postnatal days (PNDs) 1-4], at daily doses of 0.1 or 0.2 mg/kg, spanning the threshold for barely detectable cholinesterase inhibition and systemic effects. METHODS: We assessed neurochemical indices related to the function of acetylcholine (ACh) synapses (choline acetyltransferase, presynaptic high-affinity choline transporter, nicotinic cholinergic receptors) in brain regions comprising all the major ACh projections, with determinations carried out from adolescence to adulthood (PNDs 30, 60, and 100). RESULTS: Parathion exposure elicited lasting alterations in ACh markers in the frontal/parietal cortex, temporal/occipital cortex, midbrain, hippocampus, and striatum. In cerebrocortical areas, midbrain, and hippocampus, effects in males were generally greater than in females, whereas in the striatum, females were targeted preferentially. Superimposed on this general pattern, the cerebrocortical effects showed a nonmonotonic dose-response relationship, with regression of the defects at the higher parathion dose; this relationship has been seen also after comparable treatments with chlorpyrifos and diazinon and likely represents the involvement of cholinesterase-related actions that mask or offset the effects of lower doses. CONCLUSIONS: Neonatal exposure to parathion, at doses straddling the threshold for cholinesterase inhibition, compromises indices of ACh synaptic function in adolescence and adulthood. Differences between the effects of parathion compared with chlorpyrifos or diazinon and the non-monotonic dose-effect relationships reinforce the conclusion that various organophosphates diverge in their effects on neurodevelopment, unrelated to their anticholinesterase actions.

Authors
Slotkin, TA; Bodwell, BE; Ryde, IT; Levin, ED; Seidler, FJ
MLA Citation
Slotkin, TA, Bodwell, BE, Ryde, IT, Levin, ED, and Seidler, FJ. "Exposure of neonatal rats to parathion elicits sex-selective impairment of acetylcholine systems in brain regions during adolescence and adulthood." Environ Health Perspect 116.10 (October 2008): 1308-1314.
PMID
18941570
Source
pubmed
Published In
Environmental health perspectives
Volume
116
Issue
10
Publish Date
2008
Start Page
1308
End Page
1314
DOI
10.1289/ehp.11451

Idazoxan blocks the nicotine-induced reversal of the memory impairment caused by the NMDA glutamate receptor antagonist dizocilpine.

RATIONALE: Alpha2-adrenoreceptor (alpha(2)-AR) antagonists have been shown to improve, while alpha(2)-AR agonists impair cognitive function in subjects with functioning NMDA receptors (NMDAR). In subjects with inhibited NMDAR (a model of schizophrenia) alpha(2)-AR agonists attenuate the cognitive impairments. The effect with alpha(2)-AR antagonists remains unclear. OBJECTIVES: We investigated the effects of the alpha(2)-AR antagonist idazoxan on memory function in rats treated/not treated with NMDAR antagonist dizocilpine or a combination of dizocilpine and nicotine to clarify noradrenergic/cholinergic regulation of memory function. METHODS: Female Sprague-Dawley rats (n=12) were trained for food reward on the radial maze. Working and reference memory errors and response latency were assessed after injections of idazoxan (0.5, 1.0 mg/kg), dizocilpine (0.05 mg/kg), nicotine (0.2, 0.4 mg/kg) or vehicle, alone or in combination. RESULTS: Dizocilpine potently impaired memory. Nicotine (0.4 mg/kg) reversed this impairment. Idazoxan at the doses tested did not affect performance when given alone or with dizocilpine, but it did block the nicotine reversal of the dizocilpine-induced memory impairment. Three rats after 10-12 drug treatments developed limbic seizures. Our findings suggest that combination of drugs which block alpha(2)-AR with nicotinic agonists in schizophrenia may prevent therapeutic effect of nicotinic agonists and increase risk for convulsive activity with repeated administration.

Authors
Timofeeva, OA; Levin, ED
MLA Citation
Timofeeva, OA, and Levin, ED. "Idazoxan blocks the nicotine-induced reversal of the memory impairment caused by the NMDA glutamate receptor antagonist dizocilpine." Pharmacol Biochem Behav 90.3 (September 2008): 372-381.
PMID
18456310
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
90
Issue
3
Publish Date
2008
Start Page
372
End Page
381
DOI
10.1016/j.pbb.2008.03.011

Neonatal 6-hydroxydopamine lesions of the frontal cortex in rats: persisting effects on locomotor activity, learning and nicotine self-administration.

Dopaminergic innervation of the frontal cortex in adults is important for a variety of cognitive functions and behavioral control. However, the role of frontal cortical dopaminergic innervation for neurobehavioral development has received little attention. In the current study, rats were given dopaminergic lesions in the frontal cortex with local micro-infusions of 6-hydroxydopamine (6-OHDA) at 1 week of age. The long-term behavioral effects of neonatal frontal cortical 6-OHDA lesions were assessed in a series of tests of locomotor activity, spatial learning and memory, and i.v. nicotine self-administration. In addition, neurochemical indices were assessed with tissue homogenization and HPLC in the frontal cortex, striatum, and nucleus accumbens of neonatal and adult rats after neonatal 6-OHDA lesions. In neonatal rats, frontal 6-OHDA lesions as intended caused a significant reduction in frontal cortical dopamine without effects on frontal cortical 5-HT and norepinephrine. The frontal cortical dopamine depletion increased 5-HT and norepinephrine levels in the nucleus accumbens. Locomotor activity assessment during adulthood in the figure-8 maze showed that lesioned male rats were hyperactive relative to sham-lesioned males. Locomotor activity of female rats was not significantly affected by the neonatal frontal 6-OHDA lesion. Learning and memory in the radial-arm maze was also affected by neonatal frontal 6-OHDA lesions. There was a general trend toward impaired performance in early maze acquisition and a paradoxical improvement at the end of cognitive testing. Nicotine self-administration showed significant lesion x sex interactions. The sex difference in nicotine self-administration with females self-administering significantly more nicotine than males was reversed by neonatal 6-OHDA frontal cortical lesions. Neurochemical studies in adult rats showed that frontal cortical dopamine and DOPAC levels significantly correlated with nicotine self-administration in the 6-OHDA-lesioned animals but not in the controls. Frontal cortical 5-HT and 5HIAA showed inverse correlations with nicotine self-administration in the 6-OHDA-lesioned animals but not in the controls. These results show that interfering with normal dopamine innervation of the frontal cortex during early postnatal development has persisting behavioral effects, which are sex-specific.

Authors
Rezvani, AH; Eddins, D; Slade, S; Hampton, DS; Christopher, NC; Petro, A; Horton, K; Johnson, M; Levin, ED
MLA Citation
Rezvani, AH, Eddins, D, Slade, S, Hampton, DS, Christopher, NC, Petro, A, Horton, K, Johnson, M, and Levin, ED. "Neonatal 6-hydroxydopamine lesions of the frontal cortex in rats: persisting effects on locomotor activity, learning and nicotine self-administration." Neuroscience 154.3 (June 26, 2008): 885-897.
PMID
18511204
Source
pubmed
Published In
Neuroscience
Volume
154
Issue
3
Publish Date
2008
Start Page
885
End Page
897
DOI
10.1016/j.neuroscience.2008.04.020

Liver genomic responses to ciguatoxin: evidence for activation of phase I and phase II detoxification pathways following an acute hypothermic response in mice.

Ciguatoxins (CTX) are polyether neurotoxins that target voltage-gated sodium channels and are responsible for ciguatera, the most common fish-borne food poisoning in humans. This study characterizes the global transcriptional response of mouse liver to a symptomatic dose (0.26 ng/g) of the highly potent Pacific ciguatoxin-1 (P-CTX-1). At 1 h post-exposure 2.4% of features on a 44K whole genome array were differentially expressed (p < or = 0.0001), increasing to 5.2% at 4 h and decreasing to 1.4% by 24 h post-CTX exposure. Data were filtered (/fold change/ > or = 1.5 and p < or = 0.0001 in at least one time point) and a trend set of 1550 genes were used for further analysis. Early gene expression was likely influenced prominently by an acute 4 degrees C decline in core body temperature by 1 h, which resolved by 8 h following exposure. An initial downregulation of 32 different solute carriers, many involved in sodium transport, was observed. Differential gene expression in pathways involving eicosanoid biosynthesis and cholesterol homeostasis was also noted. Cytochrome P450s (Cyps) were of particular interest due to their role in xenobiotic metabolism. Twenty-seven genes, mostly members of Cyp2 and Cyp4 families, showed significant changes in expression. Many Cyps underwent an initial downregulation at 1 h but were quickly and strongly upregulated at 4 and 24 h post-exposure. In addition to Cyps, increases in several glutathione S-transferases were observed, an indication that both phase I and phase II metabolic reactions are involved in the hepatic response to CTX in mice.

Authors
Morey, JS; Ryan, JC; Bottein Dechraoui, M-Y; Rezvani, AH; Levin, ED; Gordon, CJ; Ramsdell, JS; Van Dolah, FM
MLA Citation
Morey, JS, Ryan, JC, Bottein Dechraoui, M-Y, Rezvani, AH, Levin, ED, Gordon, CJ, Ramsdell, JS, and Van Dolah, FM. "Liver genomic responses to ciguatoxin: evidence for activation of phase I and phase II detoxification pathways following an acute hypothermic response in mice." Toxicol Sci 103.2 (June 2008): 298-310.
PMID
18353800
Source
pubmed
Published In
Toxicological Sciences (Elsevier)
Volume
103
Issue
2
Publish Date
2008
Start Page
298
End Page
310
DOI
10.1093/toxsci/kfn055

Chronic nicotine and dizocilpine effects on nicotinic and NMDA glutamatergic receptor regulation: interactions with clozapine actions and attentional performance in rats.

Blockade of NMDA glutamate receptors with dizocilpine (MK-801) has been shown to cause substantial cognitive deficits and has been used to model symptoms of schizophrenia. Nicotine or nicotinic agonists, in contrast, may enhance cognitive or attentional functions and be of therapeutic potential in schizophrenia. Nicotinic-glutamatergic interactions, therefore, may have important implications in cognitive functions and antipsychotic treatments. Clozapine, a widely used antipsychotic drug, has been shown in some studies to be effective in ameliorating the cognitive deficits associated with schizophrenia. However, there is some evidence to suggest that clozapine similar to haloperidol may impair sustained attention in rats. In this study, we sought to determine whether chronic nicotine or dizocilpine may modify the effects of acute clozapine on attentional parameters and whether the behavioral effects would correlate with nicotinic or NMDA receptor densities in discrete brain regions. Adult female rats trained on an operant visual signal detection task were given 4 weeks of nicotine (5 mg/kg/day), dizocilpine (0.15 mg/kg/day), the same doses of both nicotine and dizocilpine as a mixture, or saline by osmotic minipump. While on chronic treatment, rats received acute injections of various doses of clozapine (0, 0.625, 1.25, 2.5 mg/kg, sc) 10 min prior to tests on attentional tasks. The pumps were removed on day 28 and 24 h later the animals were sacrificed for measurements of receptor densities in specific brain regions. The percent correct hit as a measure of sustained attention was significantly impaired by clozapine in a dose-related manner. Neither chronic nicotine nor dizocilpine affected this measure on their own or modified the effects of clozapine. Both nicotine and dizocilpine affected the receptor bindings in a region specific manner and their combination further modified the effects of each other in selective regions. Attentional performance was inversely correlated with alpha-bungarotoxin binding in the frontal cortex only. In conclusion, the data suggest attentional impairments with clozapine alone and no modification of this effect with nicotine or dizocilpine. Moreover, cortical low affinity nicotinic receptors may have a role in attentional functions.

Authors
Rezvani, AH; Tizabi, Y; Getachew, B; Hauser, SR; Caldwell, DP; Hunter, C; Levin, ED
MLA Citation
Rezvani, AH, Tizabi, Y, Getachew, B, Hauser, SR, Caldwell, DP, Hunter, C, and Levin, ED. "Chronic nicotine and dizocilpine effects on nicotinic and NMDA glutamatergic receptor regulation: interactions with clozapine actions and attentional performance in rats." Prog Neuropsychopharmacol Biol Psychiatry 32.4 (May 15, 2008): 1030-1040.
PMID
18343006
Source
pubmed
Published In
Progress in Neuro-Psychopharmacology & Biological Psychiatry
Volume
32
Issue
4
Publish Date
2008
Start Page
1030
End Page
1040
DOI
10.1016/j.pnpbp.2008.01.018

Repeat exposure to ciguatoxin leads to enhanced and sustained thermoregulatory, pain threshold and motor activity responses in mice: relationship to blood ciguatoxin concentrations.

Ciguatera is a common illness in tropical and subtropical regions that manifests in complex and long-lived symptoms which are more severe in subsequent exposures. This study measures central and peripheral neurologic signs, in parallel with blood toxin levels, in mice exposed once or twice (at 3 days interval) to a sublethal dose of ciguatoxin P-CTX-1 (0.26ng/g via i.p.). Mice were implanted with radiotransmitters to monitor motor activity and core temperature. A single exposure to ciguatoxin elicited an immediate and transient decrease in motor activity and temperature, and subsequent long-lasting thermoregulatory dysfunction resulting in stabilized body temperature around 36.0 degrees C with no observable circadian rhythm. The hypothermic response and the reduced activity were enhanced with a second exposure with 30% of the mice dying within 7h. Measurement of the peripheral nervous system by the tail flick assay revealed increased latency with a single ciguatoxin exposure, and a greater effect following the second exposure. Toxin was measurable in blood up to 3 days following the first exposure; at the 1h time point the concentrations were significantly elevated after a second exposure. These findings indicate an early response to ciguatoxin manifest in a central response to lower body temperature and reduce motor activity and a more persistent effect on the peripheral system leading to spinal heat antinociception and delayed fever-like response. The greater neurological response to a second ciguatoxin exposure was associated with elevated concentrations of ciguatoxin in the blood solely over the first hour of exposure. In conclusion, a single exposure to toxin exerts a significant neurological response which may be enhanced with subsequent exposure.

Authors
Bottein Dechraoui, M-Y; Rezvani, AH; Gordon, CJ; Levin, ED; Ramsdell, JS
MLA Citation
Bottein Dechraoui, M-Y, Rezvani, AH, Gordon, CJ, Levin, ED, and Ramsdell, JS. "Repeat exposure to ciguatoxin leads to enhanced and sustained thermoregulatory, pain threshold and motor activity responses in mice: relationship to blood ciguatoxin concentrations." Toxicology 246.1 (April 3, 2008): 55-62.
PMID
18280027
Source
pubmed
Published In
TOXICOLOGY
Volume
246
Issue
1
Publish Date
2008
Start Page
55
End Page
62
DOI
10.1016/j.tox.2007.12.013

Developmental neurotoxicity of low dose diazinon exposure of neonatal rats: effects on serotonin systems in adolescence and adulthood.

The developmental neurotoxicity of organophosphate pesticides targets serotonin (5HT) systems, which are involved in emotional and appetitive behaviors. We exposed neonatal rats to daily doses of diazinon on postnatal days 1-4, using doses (0.5 or 2mg/kg) spanning the threshold for barely-detectable cholinesterase inhibition. We then evaluated the effects on 5HT(1A) and 5HT(2) receptors, and on the 5HT transporter in cerebral cortical regions and the brainstem in adolescence through adulthood. Diazinon evoked a lasting deficit in 5HT(1A) receptors in males only, whereas it caused a small but significant increase in 5HT transporters in females; neither effect showed a significant regional selectivity. This pattern differed substantially from that seen in earlier work with another organophosphate, chlorpyrifos, which at pharmacodynamically similar doses spanning the threshold for cholinesterase inhibition, evoked a much more substantial, global upregulation of 5HT receptor expression; with chlorpyrifos, effects on receptors were seen in females, albeit to a lesser extent than in males, and were also regionally distinct. The effects of diazinon were nonmonotonic, showing larger alterations at the lower dose, likely reflecting positive trophic effects of cholinergic stimulation once the threshold for cholinesterase inhibition is exceeded. Our results reinforce the idea that different organophosphates have fundamentally distinct effects on the developmental trajectories of specific neurotransmitter systems, unrelated to their shared action as cholinesterase inhibitors. The effects on 5HT circuits expand the scope of behavioral endpoints that need to be considered in evaluating the developmental neurotoxicity of organophosphates.

Authors
Slotkin, TA; Ryde, IT; Levin, ED; Seidler, FJ
MLA Citation
Slotkin, TA, Ryde, IT, Levin, ED, and Seidler, FJ. "Developmental neurotoxicity of low dose diazinon exposure of neonatal rats: effects on serotonin systems in adolescence and adulthood." Brain Res Bull 75.5 (March 28, 2008): 640-647.
PMID
18355640
Source
pubmed
Published In
Brain Research Bulletin
Volume
75
Issue
5
Publish Date
2008
Start Page
640
End Page
647
DOI
10.1016/j.brainresbull.2007.10.008

Neonatal exposure to low doses of diazinon: long-term effects on neural cell development and acetylcholine systems.

BACKGROUND: The developmental neurotoxicity of organophosphate pesticides involves mechanisms other than their shared property of cholinesterase inhibition. OBJECTIVES: We gave diazinon (DZN) to newborn rats on postnatal days 1-4, using doses (0.5 or 2 mg/kg) spanning the threshold for barely detectable cholinesterase inhibition. METHODS: We then evaluated the lasting effects on indices of neural cell number and size, and on functional markers of acetylcholine (ACh) synapses (choline acetyltransferase, presynaptic high-affinity choline transporter, nicotinic cholinergic receptors) in a variety of brain regions. RESULTS: DZN exposure produced a significant overall increase in cell-packing density in adolescence and adulthood, suggestive of neuronal loss and reactive gliosis; however, some regions (temporal/occipital cortex, striatum) showed evidence of net cell loss, reflecting a greater sensitivity to neurotoxic effects of DZN. Deficits were seen in ACh markers in cerebrocortical areas and the hippocampus, regions enriched in ACh projections. In contrast, there were no significant effects in the midbrain, the major locus for ACh cell bodies. The striatum showed a unique pattern, with robust initial elevations in the ACh markers that regressed in adulthood to normal or subnormal values. CONCLUSIONS: These results indicate that developmental exposures to apparently nontoxic doses of DZN compromise neural cell development and alter ACh synaptic function in adolescence and adulthood. The patterns seen here differ substantially from those seen in earlier work with chlorpyrifos, reinforcing the concept that the various organophosphates have fundamentally different effects on the developmental trajectories of specific neurotransmitter systems, unrelated to their shared action as cholinesterase inhibitors.

Authors
Slotkin, TA; Bodwell, BE; Levin, ED; Seidler, FJ
MLA Citation
Slotkin, TA, Bodwell, BE, Levin, ED, and Seidler, FJ. "Neonatal exposure to low doses of diazinon: long-term effects on neural cell development and acetylcholine systems." Environ Health Perspect 116.3 (March 2008): 340-348.
PMID
18335101
Source
pubmed
Published In
Environmental health perspectives
Volume
116
Issue
3
Publish Date
2008
Start Page
340
End Page
348
DOI
10.1289/ehp.11005

Mercury-induced cognitive impairment in metallothionein-1/2 null mice.

Metallothioneins are central for the metabolism and detoxification of transition metals. Exposure to mercury during early neurodevelopment is associated with neurocognitive impairment. Given the importance of metallothioneins in mercury detoxification, metallothioneins may be a protective factor against mercury-induced neurocognitive impairment. Deletion of the murine metallothionein-1 and metallothionein-2 genes causes choice accuracy impairments in the 8-arm radial maze. We hypothesize that deletions of metallothioneins genes will make metallothionein-null mice more vulnerable to mercury-induced cognitive impairment. We tested this hypothesis by exposing MT1/MT2-null and wild-type mice to developmental mercury (HgCl(2)) and evaluated the resultant effects on cognitive performance on the 8-arm radial maze. During the early phase of learning metallothionein-null mice were more susceptible to mercury-induced impairment compared to wildtype mice. Neurochemical analysis of the frontal cortex revealed that serotonin levels were higher in metallothionein-null mice compared to wild-type mice. This effect was independent of mercury exposure. However, dopamine levels in mercury-exposed metallothionein-null mice were lower compared to mercury-exposed wild-type mice. This work shows that deleting metallothioneins increase the vulnerability to developmental mercury-induced neurocognitive impairment. Metallothionein effects on monoamine transmitters may be related to this cognitive effect.

Authors
Eddins, D; Petro, A; Pollard, N; Freedman, JH; Levin, ED
MLA Citation
Eddins, D, Petro, A, Pollard, N, Freedman, JH, and Levin, ED. "Mercury-induced cognitive impairment in metallothionein-1/2 null mice." Neurotoxicol Teratol 30.2 (March 2008): 88-95.
PMID
18226494
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
30
Issue
2
Publish Date
2008
Start Page
88
End Page
95
DOI
10.1016/j.ntt.2007.12.005

Nicotine and clozapine effects on attentional performance impaired by the NMDA antagonist dizocilpine in female rats.

Cognitive impairment is very prevalent in schizophrenia and is currently undertreated in most patients. Attentional deficit is one of the hallmark symptoms of schizophrenia. Antipsychotic drugs, which can be quite effective in combating hallucinations are often ineffective in reducing cognitive impairment and can potentiate cognitive impairment. Previously, we found that the antipsychotic drug clozapine impaired, while nicotine improved, the accuracy of rats performing a visual signal detection attentional task in normal rats. For the current study, in a model of cognitive impairment of schizophrenia with the NMDA antagonist dizocilpine (0.05 mg/kg), we examined the effects of clozapine and nicotine on significantly impaired attentional hit accuracy. This dizocilpine-induced impairment was significantly (p<0.05) reversed by either clozapine (1.25 mg/kg) or nicotine (0.025 mg/kg). Interestingly, when clozapine and nicotine were given together, they blocked each other's beneficial effects. When the effective doses of 1.25 mg/kg clozapine and 0.025 mg/kg nicotine were given together the combination no longer significantly reversed the dizocilpine-induced hit-accuracy impairment. Given that the great majority of people with schizophrenia smoke, the potential beneficial effects of clozapine on attentional function may be largely blocked by self-administered nicotine. In addition, there are promising results concerning the development of nicotinic treatments to reverse cognitive deficits including attentional impairment. This is supported in the current study by the reversal of the dizocilpine-induced attentional impairment by nicotine. However, in schizophrenia the efficacy of nicotinic treatments may be limited by co-treatment with antipsychotic drugs like clozapine. It will be important to determine which of the complex effects of clozapine and nicotine are key in reversing attentional impairment and how they block each other's effects for the development of therapy to combat the attentional impairment of schizophrenia.

Authors
Rezvani, AH; Kholdebarin, E; Dawson, E; Levin, ED
MLA Citation
Rezvani, AH, Kholdebarin, E, Dawson, E, and Levin, ED. "Nicotine and clozapine effects on attentional performance impaired by the NMDA antagonist dizocilpine in female rats." Int J Neuropsychopharmacol 11.1 (February 2008): 63-70.
PMID
17295931
Source
pubmed
Published In
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)
Volume
11
Issue
1
Publish Date
2008
Start Page
63
End Page
70
DOI
10.1017/S1461145706007528

Developmental diazinon neurotoxicity in rats: later effects on emotional response.

Developmental exposure to the organophosphorus pesticides chlorpyrifos and diazinon (DZN) alters serotonergic synaptic function at doses below the threshold for cholinesterase inhibition, however there are some indications that the two agents may differ in several important attributes. Previously, we found that low-dose chlorpyrifos exposure in neonatal rats causes lasting changes in emotional response and in the current study we did a comparable evaluation for DZN. Male and female Sprague-Dawley rat pups (N=10-12 of each sex per treatment group) were given 0, 0.5 or 2 mg/(kg day) of DZN s.c. daily on postnatal days (PND) 1-4. These doses bracket the threshold for barely-detectable cholinesterase inhibition. Starting on PND 52, these rats began a battery of tests to assess emotional reactivity. In the elevated plus maze, there was a slight decrease in the time spent in the open arms for DZN-exposed males, while DZN-exposed females were not different from control females. In the novelty-suppressed feeding test, DZN-exposed males had significantly shorter latencies to begin eating than did control males, reducing the values to those normally seen in females. DZN-exposed rats of either sex showed reduced preference for chocolate milk in the anhedonia test that compared the consumption of chocolate milk to water. These findings show that neonatal exposures to DZN at a dose range below the threshold for cholinesterase inhibition nevertheless evokes specific, later alterations in emotional behaviors, particularly in males. The effects show not only some similarities to those of chlorpyrifos but also some differences, in keeping with neurochemical findings comparing the two agents.

Authors
Roegge, CS; Timofeeva, OA; Seidler, FJ; Slotkin, TA; Levin, ED
MLA Citation
Roegge, CS, Timofeeva, OA, Seidler, FJ, Slotkin, TA, and Levin, ED. "Developmental diazinon neurotoxicity in rats: later effects on emotional response." Brain Res Bull 75.1 (January 31, 2008): 166-172.
PMID
18158111
Source
pubmed
Published In
Brain Research Bulletin
Volume
75
Issue
1
Publish Date
2008
Start Page
166
End Page
172
DOI
10.1016/j.brainresbull.2007.08.008

Persistent cognitive alterations in rats after early postnatal exposure to low doses of the organophosphate pesticide, diazinon.

BACKGROUND: Developmental neurotoxicity of organophosphorous insecticides (OPs) involves multiple mechanisms in addition to cholinesterase inhibition. We have found persisting effects of developmental chlorpyrifos (CPF) and diazinon (DZN) on cholinergic and serotonergic neurotransmitter systems and gene expression as well as behavioral function. Both molecular/neurochemical and behavioral effects of developmental OP exposure have been seen at doses below those which cause appreciable cholinesterase inhibition. OBJECTIVES: We sought to determine if developmental DZN exposure at doses which do not produce significant acetylcholinesterase inhibition cause persisting cognitive deficits. METHODS: Rats were exposed to DZN on postnatal days 1-4 at doses (0.5 and 2 mg/kg/d) that span the threshold for cholinesterase inhibition. They were later examined with a cognitive battery tests similar to that used with CPF. RESULTS: In the T-maze DZN caused significant hyperactivity in the initial trials of the session, but not later. In a longer assessment of locomotor activity no DZN-induced changes were seen over a 1-hour session. Prepulse inhibition was reduced by DZN exposure selectively in males vs. females; DZN eliminated the sex difference present in controls. In the radial maze, the lower but not higher DZN dose significantly impaired spatial learning. This type of nonmonotonic dose-effect function has previously been seen with CPF as well. The lower dose DZN group also showed significantly greater sensitivity to the memory-impairing effects of scopolamine a muscarinic acetylcholine antagonist. CONCLUSIONS: Neonatal DZN exposure below the threshold for appreciable cholinesterase inhibition caused persisting neurocognitive deficits in adulthood. The addition of some inhibition of AChE with a higher dose reversed the cognitive impairment. This non-monotonic dose-effect function has also been seen with neurochemical effects. Some of the DZN effects on cognition resemble those seen earlier for CPF, some differ. Our data suggest that DZN and CPF affect transmitter systems supporting memory function, differently, implying participation of mechanisms other than their common inhibition of cholinesterase.

Authors
Timofeeva, OA; Roegge, CS; Seidler, FJ; Slotkin, TA; Levin, ED
MLA Citation
Timofeeva, OA, Roegge, CS, Seidler, FJ, Slotkin, TA, and Levin, ED. "Persistent cognitive alterations in rats after early postnatal exposure to low doses of the organophosphate pesticide, diazinon." Neurotoxicol Teratol 30.1 (January 2008): 38-45.
PMID
18096363
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
30
Issue
1
Publish Date
2008
Start Page
38
End Page
45
DOI
10.1016/j.ntt.2007.10.002

Undertaking positive control studies as part of developmental neurotoxicity testing. A report from the ILSI Research Foundation/Risk Science Institute expert working group on neurodevelopmental endpoints

Developmental neurotoxicity testing involves functional and neurohistological assessments in offspring during and following maternal and/or neonatal exposure. Data from positive control studies are an integral component in developmental neurotoxicity risk assessments. Positive control data are crucial for evaluating a laboratory's capability to detect chemical-induced changes in measured endpoints. Positive control data are also valuable in a weight-of-evidence approach to help determine the biological significance of results and provide confidence in negative results from developmental neurotoxicity (DNT) studies. This review is a practical guide for the selection and use of positive control agents in developmental neurotoxicology. The advantages and disadvantages of various positive control agents are discussed for the endpoints in developmental neurotoxicity studies. Design issues specific to positive control studies in developmental neurotoxicity are considered and recommendations on how to interpret and report positive control data are made. Positive control studies should be conducted as an integral component of the incorporation and use of developmental neurotoxicity testing methods in laboratories that generate data used in risk decisions.

Authors
Crofton, KM; Foss, JA; Hass, U; Jensen, KF; Levin, ED; Parker, SP
MLA Citation
Crofton, KM, Foss, JA, Hass, U, Jensen, KF, Levin, ED, and Parker, SP. "Undertaking positive control studies as part of developmental neurotoxicity testing. A report from the ILSI Research Foundation/Risk Science Institute expert working group on neurodevelopmental endpoints." Neurotoxicology and Teratology 30.4 (2008): 266-287.
PMID
17681747
Source
scival
Published In
Neurotoxicology and Teratology
Volume
30
Issue
4
Publish Date
2008
Start Page
266
End Page
287
DOI
10.1016/j.ntt.2007.06.002

Metallothionein in the central nervous system: Roles in protection, regeneration and cognition.

Metallothionein (MT) is an enigmatic protein, and its physiological role remains a matter of intense study and debate 50 years after its discovery. This is particularly true of its function in the central nervous system (CNS), where the challenge remains to link its known biochemical properties of metal binding and free radical scavenging to the intricate workings of brain. In this compilation of four reports, first delivered at the 11th International Neurotoxicology Association (INA-11) Meeting, June 2007, the authors present the work of their laboratories, each of which gives an important insight into the actions of MT in the brain. What emerges is that MT has the potential to contribute to a variety of processes, including neuroprotection, regeneration, and even cognitive functions. In this article, the properties and CNS expression of MT are briefly reviewed before Dr Hidalgo describes his pioneering work using transgenic models of MT expression to demonstrate how this protein plays a major role in the defence of the CNS against neurodegenerative disorders and other CNS injuries. His group's work leads to two further questions, what are the mechanisms at the cellular level by which MT acts, and does this protein influence higher order issues of architecture and cognition? These topics are addressed in the second and third sections of this review by Dr West, and Dr Levin and Dr Eddins, respectively. Finally, Dr Aschner examines the ability of MT to protect against a specific toxicant, methylmercury, in the CNS.

Authors
West, AK; Hidalgo, J; Eddins, D; Levin, ED; Aschner, M
MLA Citation
West, AK, Hidalgo, J, Eddins, D, Levin, ED, and Aschner, M. "Metallothionein in the central nervous system: Roles in protection, regeneration and cognition." Neurotoxicology 29.3 (2008): 489-503.
PMID
18313142
Source
scival
Published In
NeuroToxicology
Volume
29
Issue
3
Publish Date
2008
Start Page
489
End Page
503
DOI
10.1016/j.neuro.2007.12.006

Metallothionein in the central nervous system: Roles in protection, regeneration and cognition

Metallothionein (MT) is an enigmatic protein, and its physiological role remains a matter of intense study and debate 50 years after its discovery. This is particularly true of its function in the central nervous system (CNS), where the challenge remains to link its known biochemical properties of metal binding and free radical scavenging to the intricate workings of brain. In this compilation of four reports, first delivered at the 11th International Neurotoxicology Association (INA-11) Meeting, June 2007, the authors present the work of their laboratories, each of which gives an important insight into the actions of MT in the brain. What emerges is that MT has the potential to contribute to a variety of processes, including neuroprotection, regeneration, and even cognitive functions. In this article, the properties and CNS expression of MT are briefly reviewed before Dr Hidalgo describes his pioneering work using transgenic models of MT expression to demonstrate how this protein plays a major role in the defence of the CNS against neurodegenerative disorders and other CNS injuries. His group's work leads to two further questions, what are the mechanisms at the cellular level by which MT acts, and does this protein influence higher order issues of architecture and cognition? These topics are addressed in the second and third sections of this review by Dr West, and Dr Levin and Dr Eddins, respectively. Finally, Dr Aschner examines the ability of MT to protect against a specific toxicant, methylmercury, in the CNS. © 2008 Elsevier Inc. All rights reserved.

Authors
West, AK; Hidalgo, J; Eddins, D; Levin, ED; Aschner, M
MLA Citation
West, AK, Hidalgo, J, Eddins, D, Levin, ED, and Aschner, M. "Metallothionein in the central nervous system: Roles in protection, regeneration and cognition." NeuroToxicology 29.3 (2008): 488-502.
Source
scival
Published In
NeuroToxicology
Volume
29
Issue
3
Publish Date
2008
Start Page
488
End Page
502
DOI
10.1016/j.neuro.2007.12.006

Sazetidine-A, a nicotinic desensitizing agent, decreases nicotine self-administration in rats

Authors
Levin, ED; Hampton, D; Xiao, Y; Kellar, KJ
MLA Citation
Levin, ED, Hampton, D, Xiao, Y, and Kellar, KJ. "Sazetidine-A, a nicotinic desensitizing agent, decreases nicotine self-administration in rats." October 15, 2007.
Source
wos-lite
Published In
Biochemical Pharmacology
Volume
74
Issue
8
Publish Date
2007
Start Page
SMA43
End Page
SMA44

Nicotinic interactions with antipsychotic drugs, models of schizophrenia and impacts on cognitive function.

People with schizophrenia often have substantial cognitive impairments, which may be related to nicotinic receptor deficits, (alpha7 and alpha4beta2), documented in the brains of people with schizophrenia. The large majority of people with schizophrenia smoke cigarettes. Thus, nicotinic interactions with antipsychotic drugs are widespread. Complementary co-therapies of novel nicotinic ligands are being developed to add to antipsychotic therapy to treat the cognitive impairment of schizophrenia. Thus, it is critical to understand the interaction between nicotinic treatments and antipsychotic drugs. Nicotinic interactions with antipsychotic drugs, are complex since both nicotine and antipsychotics have complex actions. Nicotine stimulates and desensitizes nicotinic receptors of various subtypes and potentiates the release of different neurotransmitters. Antipsychotics also act on a verity of receptor systems. For example, clozapine acts as an antagonist at a variety of neurotransmitter receptors such as those for dopamine, serotonin, norepinepherine and histamine. In a series of studies, we have found that in normally functioning rats, moderate doses of clozapine impair working memory and that clozapine blocks nicotine-induced memory and attentional improvement. Clozapine and nicotine can attenuate each other's beneficial effects in reversing the memory impairment caused by the psychototmimetic drug dizocilpine. A key to the clozapine-induced attenuation of nicotine-induced cognitive improvement appears to be its 5HT(2) antagonist properties. The selective 5HT(2) antagonist ketanserin has a similar action of blocking nicotine-induced memory and attentional improvements. It is important to consider the interactions between nicotinic and antipsychotic drugs to develop the most efficacious treatment for cognitive improvement in people with schizophrenia.

Authors
Levin, ED; Rezvani, AH
MLA Citation
Levin, ED, and Rezvani, AH. "Nicotinic interactions with antipsychotic drugs, models of schizophrenia and impacts on cognitive function." Biochem Pharmacol 74.8 (October 15, 2007): 1182-1191. (Review)
PMID
17714691
Source
pubmed
Published In
Biochemical Pharmacology
Volume
74
Issue
8
Publish Date
2007
Start Page
1182
End Page
1191
DOI
10.1016/j.bcp.2007.07.019

Interaction of nicotinic and histamine H(3) systems in the radial-arm maze repeated acquisition task.

Nicotinic systems have been found in a variety of studies to play important roles in cognitive function. Nicotinic involvement in different aspects of cognitive function such as learning vs. memory may differ. We have found in rats that the spatial repeated acquisition task in the radial-arm maze is significantly improved by low doses of the nicotinic receptor antagonist mecamylamine, the atypical nicotinic receptor ligand lobeline, as well as the alpha7 nicotinic receptor agonist ARR-17779. Interestingly, nicotine in the same dose range that improves working memory in the win-shift radial maze task was not effective in improving repeated acquisition performance. Nicotinic systems interact with a variety of other neural systems. Differential involvement of these extended effects with learning vs. memory may help explain differential effects of nicotinic drugs with these cognitive functions. Histamine H(3) receptor antagonists have been shown by some studies to improve cognitive function, but others have not found this effect and some have found impairment. Nicotine stimulates the release of histamine. This effect may counter other cascading effects of nicotine in the performance of learning and memory tasks. A specific test of this hypothesis involves our study of nicotine (0.1-0.4 mg/kg) interactions with the histamine H(3) receptor antagonist thioperamide (2.5-10 mg/kg) on learning memory in the repeated acquisition test in the radial-arm maze. The highest dose of thioperamide tested caused a significant choice accuracy impairment, which was most evident during the later portions of the learning curve. The highest dose of nicotine did not change overall errors but did cause a significant impairment in learning over trials. The choice accuracy impairment induced by thioperamide was significantly attenuated by nicotine (0.4 mg/kg). The learning impairment caused by the highest dose of nicotine was significantly attenuated by thioperamide. Thioperamide also caused a slowing of response, an effect, which was attenuated by nicotine co-administration. The repeated acquisition test can help differentiate acute drug effects on learning. Nicotine and thioperamide effectively reversed each other's choice accuracy impairment even though each by itself impaired accuracy.

Authors
Kholdebarin, E; Caldwell, DP; Blackwelder, WP; Kao, M; Christopher, NC; Levin, ED
MLA Citation
Kholdebarin, E, Caldwell, DP, Blackwelder, WP, Kao, M, Christopher, NC, and Levin, ED. "Interaction of nicotinic and histamine H(3) systems in the radial-arm maze repeated acquisition task." Eur J Pharmacol 569.1-2 (August 13, 2007): 64-69.
PMID
17544392
Source
pubmed
Published In
European Journal of Pharmacology
Volume
569
Issue
1-2
Publish Date
2007
Start Page
64
End Page
69
DOI
10.1016/j.ejphar.2007.04.051

Adolescent vs. adult-onset nicotine self-administration in male rats: duration of effect and differential nicotinic receptor correlates.

Adolescence is the life stage when tobacco addiction typically begins. Adolescent neurobehavioral development may be altered by nicotine self-administration in a way that persistently potentiates addiction. Previously, we showed that female adolescent rats self-administer more nicotine than do adults and that the increased nicotine intake then persists through the transition to adulthood [E.D. Levin, A. Rezvani, D. Montoya, J. Rose, H. Swartzwelder, Adolescent-onset nicotine self-administration modeled in female rats, Psychopharmacology 169 (2003) 141-149.]. In the current study, male Sprague-Dawley rats were given access to nicotine via the standard operant IV self-administration procedure (nicotine bitartrate dose of 0.03 mg/kg/infusion). One group of male rats started during adolescence the other group started in young adulthood. After the end of the four-week period of self-administration brain regions of the rats were assessed for alpha4beta2 nicotinic receptor binding. We found that male rats, like females, show higher nicotine self-administration when starting during adolescence as compared to starting in adulthood (p<0.001). Indeed, the effect in adolescent males was even greater than that in females, with more than triple the rate of nicotine self-administration vs. the adult-onset group during the first 2 weeks. The adolescent onset nicotine-self-administering rats also had significantly greater high affinity nicotinic receptor binding in the midbrain and the striatum, whereas hippocampal binding did not differ between the age groups. Striatal values significantly correlated with nicotine self-administration during the first 2 weeks in the adult-onset group but not the adolescent-onset rats, suggesting that the differences in self-administration may depend in part on underlying disparities in synaptic responses to nicotine. After the initial 2 weeks, nicotine self-administration in male rats declined toward adult-like levels, as the adolescent rats approached adulthood. This study showed that adolescent male rats self-administer significantly more nicotine than do male adult rats, but that adolescent-onset nicotine self-administration in male rats declines over weeks of continued use to approach adult-onset levels. In a previous study, we found that female rats also show greater nicotine self-administration with adolescent onset vs. adult onset, but that the females continued higher rates of self-administration into adulthood. Our results thus reinforce the concept that the adolescent brain is unusually receptive to the effects of nicotine in a manner that reinforces the potential for addiction.

Authors
Levin, ED; Lawrence, SS; Petro, A; Horton, K; Rezvani, AH; Seidler, FJ; Slotkin, TA
MLA Citation
Levin, ED, Lawrence, SS, Petro, A, Horton, K, Rezvani, AH, Seidler, FJ, and Slotkin, TA. "Adolescent vs. adult-onset nicotine self-administration in male rats: duration of effect and differential nicotinic receptor correlates." Neurotoxicol Teratol 29.4 (July 2007): 458-465.
PMID
17433619
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
29
Issue
4
Publish Date
2007
Start Page
458
End Page
465
DOI
10.1016/j.ntt.2007.02.002

Histamine H1 receptor involvement in prepulse inhibition and memory function: relevance for the antipsychotic actions of clozapine.

Histamine H(1) blockade is one of the more prominent actions of the multi-receptor acting antipsychotic clozapine. It is currently not known how much this H(1) antagonism of clozapine contributes to the therapeutic or adverse side effects of clozapine. The current studies with Sprague-Dawley rats were conducted to determine the participation of histaminergic H(1) receptor subtype in sensorimotor plasticity and memory function affected by clozapine using tests of prepulse inhibition (PPI) and radial-arm maze choice accuracy. The PPI impairment caused by the glutamate antagonist dizocilpine (MK-801) was significantly attenuated by clozapine. In the current project, we found that the selective H(1) antagonist pyrilamine also reversed the dizocilpine-induced impairment in PPI of tactile startle with an auditory prepulse. In the radial-arm maze (RAM), pyrilamine, like clozapine, impaired working memory and caused a significant dose-related slowing of response. Pyrilamine, however, decreased the number of reference memory errors. We have previously shown that nicotine effectively attenuates the clozapine-induced working memory impairment, but in the current study, nicotine did not significantly alter the effects of pyrilamine on the RAM. In summary, the therapeutic effect of clozapine in reversing PPI impairment was mimicked by the H(1) antagonist pyrilamine, while pyrilamine had a mixed effect on cognition. Pyrilamine impaired working memory but improved reference memory in rats. Thus, H(1) antagonism seems to play a role in part of the beneficial actions of antipsychotics, such as clozapine.

Authors
Roegge, CS; Perraut, C; Hao, X; Levin, ED
MLA Citation
Roegge, CS, Perraut, C, Hao, X, and Levin, ED. "Histamine H1 receptor involvement in prepulse inhibition and memory function: relevance for the antipsychotic actions of clozapine." Pharmacol Biochem Behav 86.4 (April 2007): 686-692.
PMID
17382376
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
86
Issue
4
Publish Date
2007
Start Page
686
End Page
692
DOI
10.1016/j.pbb.2007.02.014

Clozapine treatment reverses dizocilpine-induced deficits of pre-pulse inhibition of tactile startle response.

Pre-pulse inhibition (PPI) is a phenomenon of neurobehavioral plasticity in which the motor response to a startling sensory stimulus is inhibited by a preceding sensory stimulus of a lower intensity. The current experiment used tactile startle rather than acoustic startle to determine the generality of PPI across sensory modalities. PPI is easily modeled in experimental animals and serves as a useful method for determining the neural bases for sensorimotor plasticity, which can be disturbed in sensory modulation disorders. In the current study, female Sprague-Dawley rats were tested for tactile startle PPI after an auditory pre-pulse. The glutamate NMDA receptor antagonist dizocilpine (MK-801, 0.05 mg/kg) caused a nearly total blockade of the PPI effect (p<0.0005). The antipsychotic drug clozapine (1.25 mg/kg, p<0.001 and 2.5 mg/kg p<0.05) significantly attenuated the dizocilpine-induced PPI impairment. Interestingly, the lower clozapine dose did not by self enhance PPI and the higher clozapine dose when given alone caused a significant (p<0.05) PPI impairment relative to control. Nicotine (0.2 and 0.4 mg/kg) did not significantly interact with the other treatments, though the higher nicotine dose did show a trend toward attenuating the PPI impairment caused by the high clozapine dose. These effects were replicated in a second experiment of clozapine-dizocilpine interactions without nicotine treatment. This study shows that PPI of tactile startle is dramatically impaired by blocking NMDA activation and that the prototypic atypical antipsychotic drug clozapine can correct this deficit. This may be relevant to the action of clozapine in attenuating sensory gating deficits in schizophrenia and may point to new avenues of treatment for sensory modulation disorders in which there is excessive tactile response.

Authors
Levin, ED; Caldwell, DP; Perraut, C
MLA Citation
Levin, ED, Caldwell, DP, and Perraut, C. "Clozapine treatment reverses dizocilpine-induced deficits of pre-pulse inhibition of tactile startle response." Pharmacol Biochem Behav 86.3 (March 2007): 597-605.
PMID
17355891
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
86
Issue
3
Publish Date
2007
Start Page
597
End Page
605
DOI
10.1016/j.pbb.2007.02.005

Anxiolytic effects of nicotine in zebrafish.

Anxiolytic effects of nicotine have been documented in studies with rodents and humans. Understanding the neural basis of nicotine-induced anxiolysis can help both with developing better aids for smoking cessation as well as with the potential development of novel nicotinic ligands for treating anxiety. Complementary non-mammalian models may be useful for determining the molecular bases of nicotine effects on neurobehavioral function. The current project examined whether a zebrafish model of anxiety would be sensitive to nicotine. When zebrafish are placed in a novel environment, they dive to the bottom of the tank. In the wild, diving could help to escape predation. We tested the anxiolytic effect of nicotine on the novelty-elicited diving response and subsequent habituation. Zebrafish placed in a novel tank spent the majority of time at the bottom third of the tank during the first minute of a 5-min session and then show a gradual decrease in time spent at the tank bottom. Nicotine treatment at 100 mg/l for 3 min by immersion before testing caused a significant decrease in diving throughout the session, while 50 mg/l was effective during the first minute when the greatest bottom dwelling was seen in controls. Nicotine effects were reversed by the nicotinic antagonist mecamylamine given together with nicotine, but not when administered shortly before the test session after prior nicotine dosing. This implies that the effect of nicotine on diving was due to net stimulation at nicotinic receptors, an effect that is blocked by mecamylamine; and that once invoked, this effect is no longer dependent on continuing activation of nicotinic receptors. The effect of nicotine on diving did not seem to be the result of a general disorientation of the fish. The 100 mg/ml nicotine dose was shown in our earlier study to significantly improve spatial-discrimination learning in zebrafish. Nicotine-induced anxiolytic effects can be modeled in the zebrafish. This preparation will help in the investigation of the molecular bases of this effect.

Authors
Levin, ED; Bencan, Z; Cerutti, DT
MLA Citation
Levin, ED, Bencan, Z, and Cerutti, DT. "Anxiolytic effects of nicotine in zebrafish." Physiol Behav 90.1 (January 30, 2007): 54-58.
PMID
17049956
Source
pubmed
Published In
Physiology & Behavior
Volume
90
Issue
1
Publish Date
2007
Start Page
54
End Page
58
DOI
10.1016/j.physbeh.2006.08.026

Effects of atypical anxiolytic N-phenyl-2-[1-[3-(2-pyridinylethynyl)benzoyl]-4-piperidine]acetamide (JNJ-5234801) on alcohol intake in alcohol-preferring P rats.

BACKGROUND: N-Phenyl-2-[1-[3-(2-pyridinylethynyl)benzoyl]-4-piperidine]acetamide (JNJ-5234801) is a structurally novel atypical anxiolytic with an overall in vivo profile in animals suggestive of the potential to show anxiolytic efficacy in humans at doses that will not cause CNS-related side effects. Furthermore, unlike the benzodiazepines, JNJ-5234801 does not have an adverse interaction with ethanol even at doses 20 to 40 times the minimal effective dose in the rat elevated plus maze (MED=1.0 mg/kg, p.o.). METHODS: In the present study, JNJ-5234801 was evaluated for potential efficacy in reducing alcohol intake in alcohol-preferring rats. Alcohol-preferring P rats were allowed to drink water or alcohol (10%, v/v) in a 2-bottle choice procedure. Once stable baselines were established, the acute effects of JNJ-5234801 [(10-40 mg/kg, intraperitoneally (i.p.)] were assessed. In a separate study, chronic treatment with JNJ-5234801 (40 mg/kg once daily, i.p.) for 12 consecutive days was compared with naltrexone (20 mg/kg, twice daily, i.p.). RESULTS: There was a selective dose-dependent reduction in alcohol intake in the alcohol-preferring (P) rats after acute administration of JNJ-5234801 (10-40 mg/kg, i.p.). There were no significant effects on food or water intake. When administered subchronically, both JNJ-5234801 (40 mg/kg once daily, i.p.) and naltrexone (20 mg/kg, twice daily, i.p.) considerably reduced alcohol intake, but tolerance to the alcohol-suppressing effects appeared to occur sooner in the naltrexone-treated group. While both compounds slightly but significantly reduced food intake at the beginning, only JNJ-5234801 increased water intake and decreased alcohol preference. CONCLUSIONS: The novel atypical anxiolytic JNJ-5234801 has a favorable profile effects on alcohol intake and related measures compared with naltrexone, which is recommended for the treatment of alcoholism.

Authors
Rezvani, AH; Overstreet, DH; Levin, ED; Rosenthal, DI; Kordik, CP; Reitz, AB; Vaidya, AH
MLA Citation
Rezvani, AH, Overstreet, DH, Levin, ED, Rosenthal, DI, Kordik, CP, Reitz, AB, and Vaidya, AH. "Effects of atypical anxiolytic N-phenyl-2-[1-[3-(2-pyridinylethynyl)benzoyl]-4-piperidine]acetamide (JNJ-5234801) on alcohol intake in alcohol-preferring P rats." Alcohol Clin Exp Res 31.1 (January 2007): 57-63.
PMID
17207102
Source
pubmed
Published In
Alcoholism: Clinical and Experimental Research
Volume
31
Issue
1
Publish Date
2007
Start Page
57
End Page
63
DOI
10.1111/j.1530-0277.2006.00264.x

Transcriptional profiling of whole blood and serum protein analysis of mice exposed to the neurotoxin Pacific Ciguatoxin-1

Ciguatoxins (CTX) are a suite of cyclic polyether toxins produced by the marine dinoflagellate Gambierdiscus sp., are potent activators of voltage-gated sodium channels and a leading cause of human poisoning from food fish. This report characterizes the genomic and proteomic response in whole blood of adult male mice exposed i.p. to 264 ng/kg of the Pacific congener of CTX (P-CTX-1) at 1, 4 and 24 h. Whole genome microarray expression data were filtered by tightness of fit between replicates, fold change (1.8) and p-value (10-5), resulting in 183 annotated genes used for trending analysis, K-means clustering and ontology classification. Genes involved with cytokine signaling, proteasome complex and ribosomal function were dominant. qPCR performed on 19 genes of interest had a correlation of 0.95 to array results by Pearson's correlation coefficient. Serum protein analysis showed small but significant changes in 6 of 60 proteins assayed: Ccl2, Ccl12, CD40, IL-10, leptin and M-CSF. In large part, the gene expression was consistent with a Th2 immune response with interesting similarities to expression seen in asthmatic models. © 2007 Elsevier Inc. All rights reserved.

Authors
Ryan, JC; Dechraoui, M-YB; Morey, JS; Rezvani, A; Levin, ED; Gordon, CJ; Ramsdell, JS; Dolah, FMV
MLA Citation
Ryan, JC, Dechraoui, M-YB, Morey, JS, Rezvani, A, Levin, ED, Gordon, CJ, Ramsdell, JS, and Dolah, FMV. "Transcriptional profiling of whole blood and serum protein analysis of mice exposed to the neurotoxin Pacific Ciguatoxin-1." NeuroToxicology 28.6 (2007): 1099-1109.
PMID
17868886
Source
scival
Published In
NeuroToxicology
Volume
28
Issue
6
Publish Date
2007
Start Page
1099
End Page
1109
DOI
10.1016/j.neuro.2007.05.013

Guidelines on nicotine dose selection for in vivo research

Rationale: This review provides insight for the judicious selection of nicotine dose ranges and routes of administration for in vivo studies. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. In many cases, such discrepancies could be attributed to the complex variables comprising species-specific in vivo responses to acute or chronic nicotine exposure. Objectives: This review capitalizes on the authors' collective decades of in vivo nicotine experimentation to clarify the issues and to identify the variables to be considered in choosing a dosaging regimen. Nicotine dose ranges tolerated by humans and their animal models provide guidelines for experiments intended to extrapolate to human tobacco exposure through cigarette smoking or nicotine replacement therapies. Just as important are the nicotine dosaging regimens used to provide a mechanistic framework for acquisition of drug-taking behavior, dependence, tolerance, or withdrawal in animal models. Results: Seven species are addressed: humans, nonhuman primates, rats, mice, Drosophila, Caenorhabditis elegans, and zebrafish. After an overview on nicotine metabolism, each section focuses on an individual species, addressing issues related to genetic background, age, acute vs chronic exposure, route of administration, and behavioral responses. Conclusions: The selected examples of successful dosaging ranges are provided, while emphasizing the necessity of empirically determined dose-response relationships based on the precise parameters and conditions inherent to a specific hypothesis. This review provides a new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine. © 2006 Springer-Verlag.

Authors
Matta, SG; Balfour, DJ; Benowitz, NL; Boyd, RT; Buccafusco, JJ; Caggiula, AR; Craig, CR; Collins, AC; Damaj, MI; Donny, EC; Gardiner, PS; Grady, SR; Heberlein, U; Leonard, SS; Levin, ED; Lukas, RJ; Markou, A; Marks, MJ; McCallum, SE; Parameswaran, N; Perkins, KA; Picciotto, MR; Quik, M; Rose, JE; Rothenfluh, A; Schafer, WR; Stolerman, IP; Tyndale, RF; Wehner, JM; Zirger, JM
MLA Citation
Matta, SG, Balfour, DJ, Benowitz, NL, Boyd, RT, Buccafusco, JJ, Caggiula, AR, Craig, CR, Collins, AC, Damaj, MI, Donny, EC, Gardiner, PS, Grady, SR, Heberlein, U, Leonard, SS, Levin, ED, Lukas, RJ, Markou, A, Marks, MJ, McCallum, SE, Parameswaran, N, Perkins, KA, Picciotto, MR, Quik, M, Rose, JE, Rothenfluh, A, Schafer, WR, Stolerman, IP, Tyndale, RF, Wehner, JM, and Zirger, JM. "Guidelines on nicotine dose selection for in vivo research." Psychopharmacology 190.3 (2007): 269-319.
PMID
16896961
Source
scival
Published In
Psychopharmacology
Volume
190
Issue
3
Publish Date
2007
Start Page
269
End Page
319
DOI
10.1007/s00213-006-0441-0

Complementary zebrarish and rat models of developmental neurobehavioral toxicity: the case of organophosphate pesticide exposure

Authors
Levin, ED; Linney, E; Slotkin, TA
MLA Citation
Levin, ED, Linney, E, and Slotkin, TA. "Complementary zebrarish and rat models of developmental neurobehavioral toxicity: the case of organophosphate pesticide exposure." 2007.
Source
wos-lite
Published In
Neurotoxicology and Teratology
Volume
29
Issue
3
Publish Date
2007
Start Page
406
End Page
406
DOI
10.1016/j.ntt.2007.03.038

Nicotinic treatment for both symptomatic relief and attenuation of cognitive decline with aging and Alzheimer's dementia.

Authors
Levin, ED
MLA Citation
Levin, ED. "Nicotinic treatment for both symptomatic relief and attenuation of cognitive decline with aging and Alzheimer's dementia." December 2006.
Source
wos-lite
Published In
NeuroToxicology
Volume
27
Issue
6
Publish Date
2006
Start Page
1162
End Page
1162

Low dose early postnatal diazinon exposure causes impaired working memory on the radial-arm maze in rats during adulthood.

Authors
Levin, ED; Roegge, C; Timofeeva, O; Seidler, FJ; Slotkin, TA
MLA Citation
Levin, ED, Roegge, C, Timofeeva, O, Seidler, FJ, and Slotkin, TA. "Low dose early postnatal diazinon exposure causes impaired working memory on the radial-arm maze in rats during adulthood." December 2006.
Source
wos-lite
Published In
NeuroToxicology
Volume
27
Issue
6
Publish Date
2006
Start Page
1165
End Page
1165

Assessing stress in zebrafish: Anxiolytic effects of nicotine

Authors
Levin, ED; Bencan, Z; Cerutti, DT
MLA Citation
Levin, ED, Bencan, Z, and Cerutti, DT. "Assessing stress in zebrafish: Anxiolytic effects of nicotine." November 2006.
Source
crossref
Published In
Neurotoxicology and Teratology
Volume
28
Issue
6
Publish Date
2006
Start Page
709
End Page
710
DOI
10.1016/j.ntt.2006.09.016

Increased nicotine self-administration following prenatal exposure in female rats.

There is a significant association between maternal cigarette smoking during pregnancy and greater subsequent risk of smoking in female offspring. In animal models, prenatal nicotine exposure causes persistent alterations in cholinergic and monoaminergic systems, both of which are important for nicotine actions underlying tobacco addiction. Accordingly, the current study was conducted to determine if there is a cause-and-effect relationship between prenatal nicotine exposure and nicotine self-administration starting in adolescence. Pregnant rats were administered nicotine (6 mg/kg/day) by osmotic minipump infusion throughout gestation and then, beginning in adolescence and continuing into adulthood, female offspring were given access to nicotine via a standard operant IV self-administration procedure (0.03 mg/kg/infusion). Gestational nicotine exposure did not alter the initial rate of nicotine self-administration. However, when animals underwent one week of forced abstinence and then had a second opportunity to self-administer nicotine, the prenatally-exposed animals showed a significantly greater rate of self-administration than did the controls. Prenatal nicotine exposure causes increased nicotine self-administration, which is revealed only when the animals are allowed to experience a period of nicotine abstinence. This supports a cause-and-effect relationship between the higher rates of smoking in the daughters of women who smoke cigarettes during pregnancy and implicates a role for nicotine in this effect. Our results further characterize the long-term liabilities of maternal smoking but also point to the potential liabilities of nicotine-based treatments for smoking cessation during pregnancy.

Authors
Levin, ED; Lawrence, S; Petro, A; Horton, K; Seidler, FJ; Slotkin, TA
MLA Citation
Levin, ED, Lawrence, S, Petro, A, Horton, K, Seidler, FJ, and Slotkin, TA. "Increased nicotine self-administration following prenatal exposure in female rats." Pharmacol Biochem Behav 85.3 (November 2006): 669-674.
PMID
17196243
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
85
Issue
3
Publish Date
2006
Start Page
669
End Page
674
DOI
10.1016/j.pbb.2006.11.006

Transdermal nicotine attenuates depression symptoms in nonsmokers: a double-blind, placebo-controlled trial.

RATIONALE: Despite established links between nicotine dependence and depression, little research has examined the effects of nicotine on depression symptoms. OBJECTIVE: This study evaluated the acute and chronic effects of transdermal nicotine in nonsmokers with baseline depression symptoms during a 4-week, double-blind, placebo-controlled trial. METHODS: Nonsmokers with scores >or=10 on the Center for Epidemiological Studies Depression scale (CES-D) were recruited from the community. Mood and cognitive performance were measured at baseline (day 0) and at 1, 8, 21, and 28 days. Participants were randomly assigned to wear a placebo or nicotine patch for 4 weeks (3.5 mg/day during weeks 1 and 4; 7 mg/day during weeks 2 and 3). The final sample consisted of 11 nonsmokers with a mean baseline CES-D score of 27.36 (SD=10.53). RESULTS: Salivary nicotine levels indicated the majority of participants were compliant with treatment. Acute nicotine did not alter mood. After adjusting for baseline values, chronic nicotine resulted in a significant decline in CES-D scores at day 8 (3.5 mg/day), but returned to placebo levels by the last visit. This return to baseline levels was coincident with a decrease in nicotine administration from 7 to 3.5 mg/day. A similar trend for improved response inhibition as measured by the Conners Continuous Performance Task was also observed. Reported side effects were infrequent and minimal. CONCLUSION: These findings suggest a role for nicotinic receptor systems in the pathophysiology of depression and that nicotinic compounds should be evaluated for treating depression symptoms.

Authors
McClernon, FJ; Hiott, FB; Westman, EC; Rose, JE; Levin, ED
MLA Citation
McClernon, FJ, Hiott, FB, Westman, EC, Rose, JE, and Levin, ED. "Transdermal nicotine attenuates depression symptoms in nonsmokers: a double-blind, placebo-controlled trial." Psychopharmacology (Berl) 189.1 (November 2006): 125-133.
PMID
16977477
Source
pubmed
Published In
Psychopharmacology
Volume
189
Issue
1
Publish Date
2006
Start Page
125
End Page
133
DOI
10.1007/s00213-006-0516-y

Ventral hippocampal alpha7 and alpha4beta2 nicotinic receptor blockade and clozapine effects on memory in female rats.

RATIONALE: Nicotinic systems in the hippocampus play important roles in memory function. Decreased hippocampal nicotinic receptor concentration is associated with cognitive impairment in schizophrenia and Alzheimer's disease. METHODS: We modeled in rats the cognitive effects of chronic decrease in hippocampal alpha7 or alpha4beta2 receptors with 4-week continuous bilateral local infusions of the alpha7 nicotinic antagonist methyllycaconitine (MLA) or the alpha4beta2 antagonist dihydro-beta-erythroidine (DHbetaE). The working memory effects of these infusions were assessed by performance on the radial-arm maze. To test the effect of antipsychotic medication, we gave acute injections of clozapine and to determine the impact of nicotine, which is widely used by people with schizophrenia approximately half of the rats received chronic systemic infusions of nicotine. RESULTS: Chronic ventral hippocampal DHbetaE infusion caused a significant (p < 0.001) working memory impairment. Acute systemic clozapine (2.5 mg/kg) caused a significant (p < 0.005) working memory impairment in rats given control aCSF hippocampal infusions. Clozapine significantly (p < 0.025) attenuated the memory deficit caused by chronic hippocampal DHbetaE infusions. Chronic ventral hippocampal infusions with MLA did not significantly affect the working memory performance in the radial-arm maze, but it did significantly (p < 0.05) potentiate the memory impairment caused by 1.25 mg/kg of clozapine. Chronic systemic nicotine did not significantly interact with these effects. CONCLUSIONS: The state of nicotinic receptor activation in the ventral hippocampus significantly affected the impact of clozapine on working memory with blockade of alpha7 nicotinic receptors potentiating clozapine-induced memory impairment and blockade of alpha4beta2 receptors reversing the clozapine effect from impairing to improving memory.

Authors
Pocivavsek, A; Icenogle, L; Levin, ED
MLA Citation
Pocivavsek, A, Icenogle, L, and Levin, ED. "Ventral hippocampal alpha7 and alpha4beta2 nicotinic receptor blockade and clozapine effects on memory in female rats." Psychopharmacology (Berl) 188.4 (November 2006): 597-604.
PMID
16715255
Source
pubmed
Published In
Psychopharmacology
Volume
188
Issue
4
Publish Date
2006
Start Page
597
End Page
604
DOI
10.1007/s00213-006-0416-1

Persistent neurobehavioral effects of early postnatal domoic acid exposure in rats.

Domoic acid (DA) is a marine biotoxin, produced by the diatom Pseudo-nitzchia spp., which has been shown to cause cognitive impairment in adults who are exposed via contaminated seafood. The neurobehavioral consequences of developmental exposure are much less well understood. In a previous study, we showed that a single prenatal exposure to DA in rats at mid-gestation caused neurobehavioral changes that persist into adulthood including increased susceptibility to the benchmark amnestic drug scopolamine. In the current study, we examined the lasting neurobehavioral consequences of DA exposure on the first day of postnatal life, a time in rats marking the completion of the major phase of neuroproliferation and corresponding to week 24 of human gestation. The effects of DA exposure at doses from 0.025-0.1 mg/kg (s.c.) twice per day on each of postnatal days 1 and 2 were compared with vehicle-treated controls and rats treated by the same protocol with 1 mg/kg of kainic acid. Following kainic acid exposure, a sex-selective effect was seen with females but not males showing a significant slowing of response latency in the radial-arm maze. The high DA dose of 0.1 mg/kg was quite toxic causing lethality in all of the offspring exposed and this group was excluded from further analysis. When the offspring in the 0.05 mg/kg DA dose group were tested, significant hypoactivity in the Figure-8 maze was observed during adolescence. No significant DA effects were seen in response latency or choice accuracy on the radial-arm maze during either acquisition or with challenge of the amnestic drug scopolamine. Early postnatal DA exposure in the rat can be lethal and sublethal exposure can cause neurobehavioral effects manifest in modest hypoactivity during the adolescent period. However, the sublethal persistent neurobehavioral toxicity appears to be less pervasive than reported effects following DA administered mid-gestation.

Authors
Levin, ED; Pang, WG; Harrison, J; Williams, P; Petro, A; Ramsdell, JS
MLA Citation
Levin, ED, Pang, WG, Harrison, J, Williams, P, Petro, A, and Ramsdell, JS. "Persistent neurobehavioral effects of early postnatal domoic acid exposure in rats." Neurotoxicol Teratol 28.6 (November 2006): 673-680.
PMID
17046199
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
28
Issue
6
Publish Date
2006
Start Page
673
End Page
680
DOI
10.1016/j.ntt.2006.08.005

Organophosphate insecticides target the serotonergic system in developing rat brain regions: disparate effects of diazinon and parathion at doses spanning the threshold for cholinesterase inhibition.

BACKGROUND: In the developing brain, serotonin (5HT) systems are among the most sensitive to disruption by organophosphates. OBJECTIVES: We exposed neonatal rats to daily doses of diazinon or parathion on postnatal days (PND)1-4 and evaluated 5HT receptors and the 5HT transporter in brainstem and forebrain on PND5, focusing on doses of each agent below the maximum tolerated dose and spanning the threshold for cholinesterase inhibition: 0.5, 1, or 2 mg/kg for diazinon, and 0.02, 0.05, and 0.1 mg/kg for parathion. RESULTS: Diazinon evoked up-regulation of 5HT1A and 5HT2 receptor expression even at doses devoid of effects on cholinesterase activity, a pattern similar to that seen earlier for another organophosphate, chlorpyrifos. In contrast, parathion decreased 5HT1A receptors, again at doses below those required for effects on cholinesterase. The two agents also differed in their effects on the 5HT transporter. Diazinon evoked a decrease in the brainstem and an increase in the forebrain, again similar to that seen for chlorpyrifos; this pattern is typical of damage of nerve terminals and reactive sprouting. Parathion had smaller, nonsignificant effects. CONCLUSIONS: Our results buttress the idea that, in the developing brain, the various organophosphates target specific neurotransmitter systems differently from each other and without the requirement for cholinesterase inhibition, their supposed common mechanism of action.

Authors
Slotkin, TA; Tate, CA; Ryde, IT; Levin, ED; Seidler, FJ
MLA Citation
Slotkin, TA, Tate, CA, Ryde, IT, Levin, ED, and Seidler, FJ. "Organophosphate insecticides target the serotonergic system in developing rat brain regions: disparate effects of diazinon and parathion at doses spanning the threshold for cholinesterase inhibition." Environ Health Perspect 114.10 (October 2006): 1542-1546.
PMID
17035140
Source
pubmed
Published In
Environmental health perspectives
Volume
114
Issue
10
Publish Date
2006
Start Page
1542
End Page
1546

Cholinergic involvement in neurocognitive function: From zebrafish to humans.

Authors
Levin, ED
MLA Citation
Levin, ED. "Cholinergic involvement in neurocognitive function: From zebrafish to humans." September 2006.
Source
wos-lite
Published In
NeuroToxicology
Volume
27
Issue
5
Publish Date
2006
Start Page
892
End Page
893

Developing nicotinic therapy for cognitive impairment of schizophrenia and aging-related dementia

Authors
Levin, ED
MLA Citation
Levin, ED. "Developing nicotinic therapy for cognitive impairment of schizophrenia and aging-related dementia." July 2006.
Source
wos-lite
Published In
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)
Volume
9
Publish Date
2006
Start Page
S126
End Page
S126

Low-dose mecamylamine improves learning of rats in the radial-arm maze repeated acquisition procedure.

The nicotinic antagonist mecamylamine has been widely shown to cause cognitive impairment. However, these effects are mainly seen with high doses. There have been scattered findings that low doses of mecamylamine can have the opposite effect. This may be due to opposite effects of low doses of mecamylamine. In the current study, an extensive dose-effect function of mecamylamine was characterized in the low-dose range. Adult female Sprague-Dawley rats were trained on a repeated acquisition procedure on an automated 8-arm radial maze. Three of the eight arms were designated as correct for any particular session. Five trials per session were run. The number of errors per trial to find the three correct arms was determined. The rats were trained on the repeated acquisition procedure for at least 18 sessions at which time they showed reliable learning each session. Then, the effect of low doses of mecamylamine between 0 and 1 mg/kg were assessed in a repeated measures counterbalanced design. This dose range of mecamylamine did not affect performance on the first trial when the rats were naïve to the array to be learned. On trials 2-5 a significant (p<.025) quadratic dose-effect function was seen over this dose range. The most substantial effect was seen with 0.125 mg/kg of mecamylamine, which caused a significant (p<.05) improvement relative to the saline control condition. The effect diminished with increasing mecamylamine doses and with the 1 mg/kg dose choice accuracy was back to control levels. This study showed that low doses of mecamylamine can effectively improve learning. A U-shaped dose-effect curve was documented. This suggests possible low-dose nicotinic antagonist lines of treatment for cognitive impairment.

Authors
Levin, ED; Caldwell, DP
MLA Citation
Levin, ED, and Caldwell, DP. "Low-dose mecamylamine improves learning of rats in the radial-arm maze repeated acquisition procedure." Neurobiol Learn Mem 86.1 (July 2006): 117-122.
PMID
16632386
Source
pubmed
Published In
Neurobiology of Learning and Memory
Volume
86
Issue
1
Publish Date
2006
Start Page
117
End Page
122
DOI
10.1016/j.nlm.2006.01.007

Nicotine-antipsychotic drugs interaction and sustained attention in rats

Authors
Rezvani, AH; Levin, ED
MLA Citation
Rezvani, AH, and Levin, ED. "Nicotine-antipsychotic drugs interaction and sustained attention in rats." July 2006.
Source
wos-lite
Published In
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)
Volume
9
Publish Date
2006
Start Page
S146
End Page
S146

Startle and prepulse inhibition as a function of background noise: a computational and experimental analysis.

Schmajuk and Larrauri [Schmajuk NA, Larrauri JA. Neural network model of prepulse inhibition. Behav Neurosci 2005;119:1546-62.] introduced a real-time model of acoustic startle, prepulse inhibition (PPI) and facilitation (PPF) in animals and humans. The model assumes that (1) positive values of changes in noise level activate an excitatory and a facilitatory pathway, and (2) absolute values of changes in noise level activate an inhibitory pathway. The model describes many known properties of the phenomena and the effect of brain lesions on startle, PPI, and PPF. The purpose of the present study is to (a) establish the magnitude of startle and PPI as a function of pulse, prepulse, and background intensity, and (b) test the model predictions regarding an inverted-U function that relates startle to the intensity of the background noise.

Authors
Schmajuk, NA; Larrauri, JA; Hagenbuch, N; Levin, ED; Feldon, J; Yee, BK
MLA Citation
Schmajuk, NA, Larrauri, JA, Hagenbuch, N, Levin, ED, Feldon, J, and Yee, BK. "Startle and prepulse inhibition as a function of background noise: a computational and experimental analysis." Behav Brain Res 170.2 (June 30, 2006): 182-196.
PMID
16569445
Source
pubmed
Published In
Behavioural Brain Research
Volume
170
Issue
2
Publish Date
2006
Start Page
182
End Page
196
DOI
10.1016/j.bbr.2006.02.021

Comparative developmental neurotoxicity of organophosphate insecticides: effects on brain development are separable from systemic toxicity.

A comparative approach to the differences between systemic toxicity and developmental neurotoxicity of organophosphates is critical to determine the degree to which multiple mechanisms of toxicity carry across different members of this class of insecticides. We contrasted neuritic outgrowth and cholinergic synaptic development in neonatal rats given different organophosphates (chlorpyrifos, diazinon, parathion) at doses spanning the threshold for impaired growth and viability. Animals were treated daily on postnatal days 1-4 by subcutaneous injection so as to bypass differences in first-pass activation to the oxon or catabolism to inactive products. Evaluations occurred on day 5. Parathion (maximum tolerated dose, 0.1 mg/kg) was far more systemically toxic than was chlorpyrifos or diazinon (maximum tolerated dose, 1-5 mg/kg). Below the maximum tolerated dose, diazinon impaired neuritic outgrowth in the forebrain and brainstem, evidenced by a deficit in the ratio of membrane protein to total protein. Diazinon also decreased choline acetyltransferase activity, a cholinergic neuronal marker, whereas it did not affect hemicholinium-3 binding to the presynaptic choline transporter, an index of cholinergic neuronal activity. There was no m(subscript)2(/subscript)-muscarinic acetylcholine receptor down-regulation, as would have occurred with chronic cholinergic hyperstimulation. The same pattern was found previously for chlorpyrifos. In contrast, parathion did not elicit any of these changes at its maximum tolerated dose. These results indicate a complete dichotomy between the systemic toxicity of organophosphates and their propensity to elicit developmental neurotoxicity. For parathion, the threshold for lethality lies below that necessary for adverse effects on brain development, whereas the opposite is true for chlorpyrifos and diazinon.

Authors
Slotkin, TA; Levin, ED; Seidler, FJ
MLA Citation
Slotkin, TA, Levin, ED, and Seidler, FJ. "Comparative developmental neurotoxicity of organophosphate insecticides: effects on brain development are separable from systemic toxicity." Environ Health Perspect 114.5 (May 2006): 746-751.
PMID
16675431
Source
pubmed
Published In
Environmental health perspectives
Volume
114
Issue
5
Publish Date
2006
Start Page
746
End Page
751

Dorsal hippocampal alpha7 and alpha4beta2 nicotinic receptors and memory.

Nicotinic receptor systems have been shown to be important for working memory. In general, nicotinic agonists have been shown to improve memory, and nicotinic antagonists impair it. All of the neuronal substrates for nicotinic involvement in memory still remain to be discovered. The amygdala and ventral hippocampus have both been found to be important for nicotinic involvement in memory function. Local infusion of the nicotinic antagonist methyllycaconitine (MLA) to block alpha7 nicotinic receptors and dihydro-beta-erythrodine (DHbetaE) to block alpha4beta2 nicotinic receptors into the basolateral amygdala and the ventral hippocampus have been found to impair working memory function, with no additive effects being observed. The current project assessed the roles of alpha7 and alpha4beta2 nicotinic receptors in the dorsal hippocampus for memory function. Adult female Sprague-Dawley rats were trained on the 16-arm radial maze. The rats (n = 10) had bilateral cannulae implanted into the dorsal hippocampus. The rats were given acute infusions of DHbetaE (0, 1.69, 3.38, and 6.75 microg/side) and MLA (6.75 microg/side) alone and in combination in a repeated measures counter-balanced design. DHbetaE and MLA infusion into the dorsal hippocampus significantly increased working memory errors. However, when the two drugs were given in combination, an attenuated effect was seen. No significant effects of MLA or DHbetaE were seen with reference memory errors or response latency. These results confirm the importance of alpha4beta2 and alpha7 nicotinic acetylcholine receptors in the dorsal hippocampus for appetitively-motivated spatial cognitive function.

Authors
Nott, A; Levin, ED
MLA Citation
Nott, A, and Levin, ED. "Dorsal hippocampal alpha7 and alpha4beta2 nicotinic receptors and memory." Brain Res 1081.1 (April 7, 2006): 72-78.
PMID
16556437
Source
pubmed
Published In
Brain Research
Volume
1081
Issue
1
Publish Date
2006
Start Page
72
End Page
78
DOI
10.1016/j.brainres.2006.01.052

Metallothionein expression and neurocognitive function in mice.

Transition metals have been associated with impaired neurological development, and neurobehavioral activity. Metallothioneins are central components in the metabolism and detoxification of a variety of metals, however, little is known concerning their role in cognitive function. To determine the role of metallothionein in learning and memory, mice with deletions of two metallothionein genes (MT-1 and MT-2) were trained on a win-shift task in an 8-arm radial maze. The parental strain of mice learned the maze at a normal rate over an 18-session acquisition period. In contrast, the MT-1/MT-2-null mice, which had a similar choice accuracy level at the beginning of training, showed a poorer rate of learning during the training period. In addition, the MT-1/MT-2-null mice showed significantly less choice accuracy than the parental strain. The MT-1/MT-2-null mice also showed a significant hypoactivity during the early and middle parts of acquisition training, but they were not different from the wildtype controls during the final phase of training. Nicotine treatment, which can improve working memory, eliminated the impairment associated with the deletion of the MT-1 and MT-2 genes in a dose-related fashion after acquisition training in the aging adult mice. These results suggest that metallothioneins, through there roles in metal physiology or cellular protection, are involved in spatial learning and memory function.

Authors
Levin, ED; Perraut, C; Pollard, N; Freedman, JH
MLA Citation
Levin, ED, Perraut, C, Pollard, N, and Freedman, JH. "Metallothionein expression and neurocognitive function in mice." Physiol Behav 87.3 (March 30, 2006): 513-518.
PMID
16430929
Source
pubmed
Published In
Physiology & Behavior
Volume
87
Issue
3
Publish Date
2006
Start Page
513
End Page
518
DOI
10.1016/j.physbeh.2005.11.014

Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization.

RATIONALE: Nicotine has been shown in a variety of studies in humans and experimental animals to improve cognitive function. Nicotinic treatments are being developed as therapeutic treatments for cognitive dysfunction. OBJECTIVES: Critical for the development of nicotinic therapeutics is an understanding of the neurobehavioral bases for nicotinic involvement in cognitive function. METHODS: Specific and diverse cognitive functions affected by nicotinic treatments are reviewed, including attention, learning, and memory. The neural substrates for these behavioral actions involve the identification of the critical pharmacologic receptor targets, in particular brain locations, and how those incipient targets integrate with broader neural systems involved with cognitive function. RESULTS: Nicotine and nicotinic agonists can improve working memory function, learning, and attention. Both alpha4beta2 and alpha7 nicotinic receptors appear to be critical for memory function. The hippocampus and the amygdala in particular have been found to be important for memory, with decreased nicotinic activity in these areas impairing memory. Nicotine and nicotinic analogs have shown promise for inducing cognitive improvement. Positive therapeutic effects have been seen in initial studies with a variety of cognitive dysfunctions, including Alzheimer's disease, age-associated memory impairment, schizophrenia, and attention deficit hyperactivity disorder. CONCLUSIONS: Discovery of the behavioral, pharmacological, and anatomic specificity of nicotinic effects on learning, memory, and attention not only aids the understanding of nicotinic involvement in the basis of cognitive function, but also helps in the development of novel nicotinic treatments for cognitive dysfunction. Nicotinic treatments directed at specific receptor subtypes and nicotinic cotreatments with drugs affecting interacting transmitter systems may provide cognitive benefits most relevant to different syndromes of cognitive impairment such as Alzheimer's disease, schizophrenia, and attention deficit hyperactivity disorder. Further research is necessary in order to determine the efficacy and safety of nicotinic treatments of these cognitive disorders.

Authors
Levin, ED; McClernon, FJ; Rezvani, AH
MLA Citation
Levin, ED, McClernon, FJ, and Rezvani, AH. "Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization." Psychopharmacology (Berl) 184.3-4 (March 2006): 523-539. (Review)
PMID
16220335
Source
pubmed
Published In
Psychopharmacology
Volume
184
Issue
3-4
Publish Date
2006
Start Page
523
End Page
539
DOI
10.1007/s00213-005-0164-7

Timing of nicotine effects on learning in zebrafish.

RATIONALE: Nicotine has been shown in many, but not all, studies to improve cognitive function in a number of species including rats, mice, monkeys, and humans. Recently, we have found that nicotine also improves memory in zebrafish. Nicotinic agonists are being developed as novel treatments for Alzheimer's disease and other cognitive impairments. OBJECTIVES: In screening the therapeutic potential of novel nicotinic agonists, it is important to have a rapid assay of cognitive improvement. Zebrafish can help with this effort. METHODS: We have developed a method of rapidly assessing spatial position discrimination learning in zebrafish in one session of seven trials. We used this method to determine the cognitive effects of nicotine. RESULTS: Nicotine (100 mg/l administered during 3 min of immersion) caused a significant improvement in percent correct performance. This dose was within the effective range we found to improve the choice accuracy performance of zebrafish using the more time-intensive delayed spatial alternation procedure. Interestingly, the positive effect of nicotine was seen at 20-40 min postadministration, but not earlier, and declined at 80 and 160 min posttreatment. At the 40-min postdosing interval, 200 mg/l nicotine was also found to significantly improve choice accuracy. Nicotine-induced accuracy improvement was reversed by the nicotinic antagonist mecamylamine given shortly before testing but not when given concurrently with nicotine. CONCLUSIONS: This position discrimination procedure in zebrafish effectively demonstrated the cognitive-enhancing effects of nicotine. This model may be useful in the early screening of novel nicotinic compounds for treatment of cognitive dysfunction.

Authors
Levin, ED; Limpuangthip, J; Rachakonda, T; Peterson, M
MLA Citation
Levin, ED, Limpuangthip, J, Rachakonda, T, and Peterson, M. "Timing of nicotine effects on learning in zebrafish." Psychopharmacology (Berl) 184.3-4 (March 2006): 547-552.
PMID
16175402
Source
pubmed
Published In
Psychopharmacology
Volume
184
Issue
3-4
Publish Date
2006
Start Page
547
End Page
552
DOI
10.1007/s00213-005-0162-9

Effects of clozapine on memory function in the rat neonatal hippocampal lesion model of schizophrenia.

Clozapine is an effective atypical antipsychotic drug used to treat schizophrenia. It has the advantage of producing fewer extrapyramidal motor side effects than typical antipsychotic drugs such as haloperidol. Schizophrenia involves more than the hallmark symptom of psychosis. Substantial cognitive impairment is also seen. Effective drug treatments against the cognitive impairment of schizophrenia need to be developed. The current study was conducted to determine the effects of clozapine on working memory in the rat neonatal hippocampal lesion model of schizophrenia, which includes symptoms of cognitive impairment. Infant Sprague-Dawley rats were given ibotenic acid lesions of the hippocampus on day 7 of age (using the day of birth as day 0). Controls were given vehicle infusions. In adulthood, the rats were trained on the 8-arm radial maze using the win-shift procedure. After 6 sessions of training, the lesioned rats and their controls were administered repeated injections of saline or clozapine (2.5 mg/kg) for the next 12 sessions of training. The females had significant radial-arm maze choice accuracy impairments caused by either clozapine or the hippocampal lesion, but the combination of the two treatments had no additive effect. The males showed a different pattern of effects. Intact males did not show a significant clozapine-induced impairment, whereas males with hippocampal lesions did show significant clozapine-induced impairment although hippocampal lesions by themselves did not significantly impair male choice accuracy. These data show that clozapine can cause memory impairment and it potentiates rather than reverses hippocampal lesion-induced deficits. There are critical sex-related differences in these effects.

Authors
Levin, ED; Christopher, NC
MLA Citation
Levin, ED, and Christopher, NC. "Effects of clozapine on memory function in the rat neonatal hippocampal lesion model of schizophrenia." Prog Neuropsychopharmacol Biol Psychiatry 30.2 (March 2006): 223-229.
PMID
16356617
Source
pubmed
Published In
Progress in Neuro-Psychopharmacology & Biological Psychiatry
Volume
30
Issue
2
Publish Date
2006
Start Page
223
End Page
229
DOI
10.1016/j.pnpbp.2005.10.018

Chronic nicotine interactions with clozapine and risperidone and attentional function in rats.

Although antipsychotic drugs are therapeutically effective in attenuating the hallmark symptoms of schizophrenia, these improvements do not return most patients to normative standards of cognitive function. Thus, complementary drug treatment may be needed to treat the attentional deficits of schizophrenia as well as to counteract the potential attentional impairments caused by some antipsychotic drugs. Nicotine, a drug commonly self-administered by a great majority of individuals with schizophrenia, has been shown to significantly improve cognitive function in some studies. The current study was conducted to determine the interactive effects of the atypical antipsychotic drugs clozapine and risperidone with chronic nicotine administration on attentional performance. Adult female Sprague-Dawley rats (N=35) were trained to perform an attentional task using an operant visual signal detection task. After training, rats were infused with a dose of 5 mg/kg/day (s.c.) nicotine base (n=18) or saline (n=17) for 28 consecutive days via osmotic pump. In Exp. 1, while being administered chronic nicotine or saline, rats were given acute doses of clozapine (0, 0.625, 1.25 and 2.5 mg/kg, s.c.) and were tested for attentional function. In Exp. 2, while on chronic nicotine or saline, other rats were challenged with acute doses of risperidone (0, 0.025, 0.05 and 0.1 mg/kg, s.c.) and were tested for attentional function. Results showed that acute administration of clozapine caused a significant dose-dependent impairment in choice accuracy (percent hit) in animals treated with chronic saline. Chronic nicotine treatment itself lowered accuracy, but attenuated further declines with acute clozapine treatment. Acute administration of risperidone at high dose significantly reduced performance (percent correct rejection) in chronically saline-treated rats, but in a similar fashion as in Exp. 1, chronic nicotine lowered accuracy but attenuated further impairment with acute risperidone. In summary, atypical antipsychotic drugs clozapine and risperidone significantly impaired choice accuracy in the visual signal detection task. Clozapine was more detrimental than risperidone but the adverse effects of both clozapine and risperidone on attentional performance were masked in rats chronically treated with nicotine.

Authors
Rezvani, AH; Caldwell, DP; Levin, ED
MLA Citation
Rezvani, AH, Caldwell, DP, and Levin, ED. "Chronic nicotine interactions with clozapine and risperidone and attentional function in rats." Prog Neuropsychopharmacol Biol Psychiatry 30.2 (March 2006): 190-197.
PMID
16310917
Source
pubmed
Published In
Progress in Neuro-Psychopharmacology & Biological Psychiatry
Volume
30
Issue
2
Publish Date
2006
Start Page
190
End Page
197
DOI
10.1016/j.pnpbp.2005.10.017

Developmental and behavioral effects of embryonic exposure to the polybrominated diphenylether mixture DE-71 in the killifish (Fundulus heteroclitus).

Exposures to penta polybrominated diphenylether (PeBDE) cause neurobehavioral toxicity in developing mice and rats. As levels of these ubiquitous contaminants are increasing in the environment, this raises concern that wildlife may also suffer such effects, with consequences for their ability to catch prey and avoid predators. PeBDE levels in wild-caught fish have been steadily escalating over the past fifteen years. To our knowledge, behavioral consequences of piscine embryonic exposure to PeBDE has not yet been studied. The objectives of this investigation were to characterize effects on development in an environmentally relevant fish model, and test for latent behavioral effects following cessation of exposure. Embryos from the estuarine minnow, Fundulus heteroclitus, were exposed from day 0-7 post fertilization to the industrial PeBDE mixture, DE-71 (0.001 to 100 microg l(-1)). Embryos were assayed for hatching success, development, and microsomal enzyme cytochrome P4501A (CYP1A) activity, which was determined by analysis of in ovo ethoxy-resorufin-O-deethylase (EROD) activation in embryos. Larval fish were assayed for predation ability, activity level, and fright response to a simulated predator. Juvenile fish were assayed for learning ability in a three-chambered fish maze. No induction of embryonic EROD activity was observed, nor was a high dose of DE-71 able to inhibit EROD activity induced by beta-naphthoflavone. No deformities were detected, but a subtle developmental asymmetry with respect to tail curvature direction was observed, and a hatching delay of up to 4.5 days was noted. Behavioral test results suggest that embryonic exposure to DE-71 may alter activity level, fright response, predation rates, and learning ability in subsequent life stages.

Authors
Timme-Laragy, AR; Levin, ED; Di Giulio, RT
MLA Citation
Timme-Laragy, AR, Levin, ED, and Di Giulio, RT. "Developmental and behavioral effects of embryonic exposure to the polybrominated diphenylether mixture DE-71 in the killifish (Fundulus heteroclitus)." Chemosphere 62.7 (February 2006): 1097-1104.
PMID
16045967
Source
pubmed
Published In
Chemosphere
Volume
62
Issue
7
Publish Date
2006
Start Page
1097
End Page
1104
DOI
10.1016/j.chemosphere.2005.05.037

The rationale for studying transmitter interactions to understand the neural bases of cognitive function.

Authors
Levin, ED
MLA Citation
Levin, ED. "The rationale for studying transmitter interactions to understand the neural bases of cognitive function." EXS 98 (2006): 1-3. (Review)
PMID
17019880
Source
pubmed
Published In
EXS
Volume
98
Publish Date
2006
Start Page
1
End Page
3

Nicotinic-antipsychotic drug interactions and cognitive function.

In summary, neuronal nicotinic systems are important for a variety of aspects of cognitive function impacted by antipsychotic drugs. It has been demonstrated that antipsychotic drugs have memory and attentional impairing effects when given to unimpaired subjects. Nicotine can reduce some of these impairments, but antipsychotic drug administration can also attenuate nicotine effects. We have found that nicotinic agonists selective for alpha7 and alpha4beta2 receptor subtypes significantly improve learning and memory. Serotonergic actions of antipsychotic drugs may decrease efficacy of nicotinic co-treatments. When the antipsychotic drug clozapine and nicotine are administered to subjects with cognitive impairments caused by NMDA glutamate receptor blockade or hippocampal dysfunction they can significantly attenuate the attentional and memory impairments. Nicotine has been shown in our studies to reverse the memory impairment caused by acute clozapine-induced memory improvement. Acute risperidone and haloperidol has been shown to attenuate nicotine-induced memory improvement. We have determined the role of hippocampal alpha7 and alpha4beta2 nicotinic receptors in the neural basis of nicotinic antipsychotic interactions. Local acute and chronic hippocampal infusion of either nicotinic alpha7 or alpha4beta2 antagonists cause significant spatial working memory impairment. Chronic hippocampal nicotinic antagonist infusions have served as a model of persistent decreases in nicotinic receptor level seen in schizophrenia and Alzheimer's disease. Clozapine attenuated the memory deficit caused by chronic suppression of hippocampal alpha4beta2 receptors while the amnestic effects of clozapine were potentiated by chronic suppression of hippocampal alpha7 receptors. Nicotinic co-treatment may be a useful adjunct in the treatment of schizophrenia, to attenuate cognitive impairment of schizophrenia. Nicotine as well as selective nicotinic alpha7 and alpha4beta2 receptor agonists significantly improve working memory and attentional function. Nicotine treatment was found to be effective in attenuating the attentional and memory impairments caused by the psychototmimetic NMDA antagonist dizocilpine (MK-801), a model of the cognitive impairment of schizophrenia. Studies of the interactions of antipsychotic drugs with nicotinic agents provided quite useful information concerning possible co-treatment of people with schizophrenia with nicotinic therapy. Nicotine was found to significantly attenuate the memory impairments caused by the antipsychotic drugs clozapine and olanzapine. Interestingly, nicotine-induced cognitive improvement was significantly attenuated by the antipsychotic drug clozapine. One of the principal effects of clozapine is to block 5HT2 receptors. Ketanserin a 5HT2 antagonist significantly attenuated nicotine-induced improvements in attention and memory. Thus it appears that antipsychotic drugs with actions blocking 5HT2 receptors may limit the efficacy of nicotinic co-treatments for cognitive enhancement.

Authors
Levin, ED; Rezvani, AH
MLA Citation
Levin, ED, and Rezvani, AH. "Nicotinic-antipsychotic drug interactions and cognitive function." EXS 98 (2006): 185-205. (Review)
PMID
17019889
Source
pubmed
Published In
EXS
Volume
98
Publish Date
2006
Start Page
185
End Page
205

Persisting effects of early postnatal diazinon exposure on emotional reactivity in rats

Authors
Roegge, C; Timofeva, O; Seidler, F; Slotkin, TA; Levin, ED
MLA Citation
Roegge, C, Timofeva, O, Seidler, F, Slotkin, TA, and Levin, ED. "Persisting effects of early postnatal diazinon exposure on emotional reactivity in rats." 2006.
Source
wos-lite
Published In
Neurotoxicology and Teratology
Volume
28
Issue
6
Publish Date
2006
Start Page
709
End Page
709
DOI
10.1016/j.ntt.2006.09.015

Clozapine effects on memory function are reversed by hippocampal damage

Authors
Levin, ED
MLA Citation
Levin, ED. "Clozapine effects on memory function are reversed by hippocampal damage." December 2005.
Source
wos-lite
Published In
Neuropsychopharmacology (Nature)
Volume
30
Publish Date
2005
Start Page
S197
End Page
S197

Mode of action: disruption of brain cell replication, second messenger, and neurotransmitter systems during development leading to cognitive dysfunction--developmental neurotoxicity of nicotine.

Developmental exposure to nicotine in rats results in neurobehavioral effects such as reduced locomotor and cognitive function. Key events in the animal mode of action (MOA) include binding to the nicotinic cholinergic receptor during prenatal and/or early postnatal development. This leads to premature onset of cell differentiation at the expense of cell replication, which leads to brain cell death or structural alterations in regional brain areas. Other events include an initial increase followed by a decrease in adenyl cyclase activity, as well as effects on the noradrenergic, dopaminergic, and serotonergic neurotransmitter systems. Because the nicotine receptor is also present in the developing human brain and the underlying biology for DNA synthesis and cell signaling is comparable, this MOA is likely to be relevant for humans. Although the effects of nicotine exposure in developing humans is not well documented, nicotine exposure as a result of cigarette smoking during pregnancy is associated with several physiological and behavioral outcomes that are reminiscent of the effects of nicotine alone in animal models. As data become available with the advent of the use of the nicotine patch in pregnant humans, the question as to the relative importance of smoking per se versus nicotine alone may be determined.

Authors
Slikker, W; Xu, ZA; Levin, ED; Slotkin, TA
MLA Citation
Slikker, W, Xu, ZA, Levin, ED, and Slotkin, TA. "Mode of action: disruption of brain cell replication, second messenger, and neurotransmitter systems during development leading to cognitive dysfunction--developmental neurotoxicity of nicotine." Crit Rev Toxicol 35.8-9 (October 2005): 703-711. (Review)
PMID
16417037
Source
pubmed
Published In
Critical Reviews in Toxicology (Informa)
Volume
35
Issue
8-9
Publish Date
2005
Start Page
703
End Page
711

Persisting behavioral consequences of prenatal domoic acid exposure in rats.

To investigate the behavioral effects of prenatal exposure to the marine toxin domoic acid, pregnant female rats were injected subcutaneously with 0, 0.3, 0.6, or 1.2 mg/kg of domoic acid on gestational day 13. The offspring were then run through a behavioral testing battery to determine the developmental effects of the toxin on spontaneous alternation in the T-maze, on locomotor activity in the Figure-8 maze, and on working memory in the 8-arm radial maze. In the T-maze, no significant domoic acid induced differences were seen on spontaneous alternation, but there were significant domoic acid effects on latency. Prenatal domoic acid exposure caused a dose-related increase in response latency in the second spontaneous alternation test. There was also a significant domoic acid effect seen in the 1-h long Figure-8 maze test. Locomotor activity measured in the Figure-8 maze detected a persisting effect of the 1.2 mg/kg domoic acid dose, which significantly increased the rate of habituation over the activity test session. This was characterized by higher initial activity followed by greater decline in activity. In the radial-arm maze the control vehicle treated rats showed the normal sex-related difference in spatial learning and memory with males outperforming females. Developmental domoic acid exposure decreased this effect such that the normal sex difference in spatial memory was not seen with the 1.2 mg/kg domoic acid dose. The rats of both sexes with a history of prenatal domoic acid exposure showed increased susceptibility to the amnestic effects of the muscarinic acetylcholine scopolamine, suggesting that they had less functional reserve with which to solve the radial-arm maze memory task. This study demonstrates persisting neurobehavioral effects of acute prenatal exposure to domoic acid at doses that do not cause overt clinical signs of toxicity.

Authors
Levin, ED; Pizarro, K; Pang, WG; Harrison, J; Ramsdell, JS
MLA Citation
Levin, ED, Pizarro, K, Pang, WG, Harrison, J, and Ramsdell, JS. "Persisting behavioral consequences of prenatal domoic acid exposure in rats." Neurotoxicol Teratol 27.5 (September 2005): 719-725.
PMID
16054336
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
27
Issue
5
Publish Date
2005
Start Page
719
End Page
725
DOI
10.1016/j.ntt.2005.06.017

Gestational dexamethasone treatment elicits sex-dependent alterations in locomotor activity, reward-based memory and hippocampal cholinergic function in adolescent and adult rats.

Glucocorticoids are the consensus treatment for preventing respiratory distress syndrome in preterm infants but there is emerging evidence of subsequent neurobehavioral abnormalities, independent of somatic growth effects. Pregnant rats were given 0.2 mg/kg of dexamethasone, a dose commensurate with clinical use, on gestational days 17-19 and behavioral evaluations were made on the offspring in adolescence and adulthood. The dexamethasone groups had the same body weights as the controls but nevertheless displayed long-term, sex-selective alterations in locomotor and cognitive behaviors. In the figure-8 activity apparatus, dexamethasone treatment ablated the normal sex differences in locomotor activity by reducing values in females to the lower level typical of males; habituation of activity similarly was impaired in females, reducing the profile to match that of control males, while male rats in the dexamethasone group showed a partially feminized pattern of habituation. In the 8-arm radial maze, control rats displayed typical sex differences, with male rats performing more accurately than females. Dexamethasone treatment eliminated this normal dichotomy, delaying learning in males while improving performance in females to the level normally seen in control males. Finally, we assessed hippocampal [3H]hemicholinium-3 binding as a biomarker for cholinergic synaptic activity, and again found loss of sex differences in the dexamethasone group: values in males were increased to the higher levels typical of females. These results indicate that gestational treatment with dexamethasone obtunds the normal sex differences in neurochemistry and behavior that are typically seen in adolescence in adulthood, thus producing sex-selective alterations in activity, learning, and memory.

Authors
Kreider, ML; Levin, ED; Seidler, FJ; Slotkin, TA
MLA Citation
Kreider, ML, Levin, ED, Seidler, FJ, and Slotkin, TA. "Gestational dexamethasone treatment elicits sex-dependent alterations in locomotor activity, reward-based memory and hippocampal cholinergic function in adolescent and adult rats." Neuropsychopharmacology 30.9 (September 2005): 1617-1623.
PMID
15812569
Source
pubmed
Published In
Neuropsychopharmacology (Nature)
Volume
30
Issue
9
Publish Date
2005
Start Page
1617
End Page
1623
DOI
10.1038/sj.npp.1300716

Adolescent vulnerabilities to chronic alcohol or nicotine exposure: findings from rodent models.

This article presents an overview of the proceedings from a symposium entitled "Is adolescence special? Possible age-related vulnerabilities to chronic alcohol or nicotine exposure," organized by Susan Barron and Linda Spear and held at the 2004 Research Society on Alcoholism Meeting in Vancouver, British Columbia. This symposium, co-sponsored by the Fetal Alcohol Syndrome Study Group and the Neurobehavioral Teratology Society, focused on our current knowledge regarding the long-term consequences of ethanol and/or nicotine exposure during adolescence with the emphasis on data from rodent models. The support from these two societies represents the understanding by these research groups that adolescence represents a unique developmental stage for the effects of chronic drug exposure and also marks an age in which many risky behaviors including alcohol consumption and smoking typically begin. The speakers included (1) Aaron White, who presented data on the effects of adolescent ethanol exposure on subsequent motor or cognitive response to an ethanol challenge in adulthood; (2) Richard Bell, who presented data suggesting that genetic differences could play a role in adolescent vulnerability to ethanol; (3) Craig Slawecki, who presented data looking at the effects of chronic exposure to alcohol or nicotine on neurophysiologic and behavioral end points; and (4) Ed Levin, who presented data on acute and long-term consequences of adolescent nicotine exposure. Finally, Linda Spear provided some summary points and recommendations regarding unresolved issues and future directions.

Authors
Barron, S; White, A; Swartzwelder, HS; Bell, RL; Rodd, ZA; Slawecki, CJ; Ehlers, CL; Levin, ED; Rezvani, AH; Spear, LP
MLA Citation
Barron, S, White, A, Swartzwelder, HS, Bell, RL, Rodd, ZA, Slawecki, CJ, Ehlers, CL, Levin, ED, Rezvani, AH, and Spear, LP. "Adolescent vulnerabilities to chronic alcohol or nicotine exposure: findings from rodent models." Alcohol Clin Exp Res 29.9 (September 2005): 1720-1725. (Review)
PMID
16205372
Source
pubmed
Published In
Alcoholism: Clinical and Experimental Research
Volume
29
Issue
9
Publish Date
2005
Start Page
1720
End Page
1725

Memory decline of aging reduced by extracellular superoxide dismutase overexpression.

Extracellular superoxide dismutase (EC-SOD) plays an important role in controlling oxidative stress as well as intercellular signaling. In the current study, we tested the effect of EC-SOD overexpression over the lifespan of a set of mice and their wild-type controls to determine the time scale over which EC-SOD overexpression might attenuate aging-induced memory impairment. Mice with overexpression of EC-SOD and wild-type controls were initially trained on the radial-arm maze as young adults (3-5 months) and then retrained during middle age (12-14 months) and retested in old age at 27 and 30 months. There was little EC-SOD effect during the young adult middle age periods. EC-SOD overexpression prevented the decline in choice accuracy when the mice were 27-30 months of age. The EC-SOD overexpressing mice maintained their performance, while the wild-type mice declined to naïve levels of performance by 30 months of age. Enhancement of EC-SOD activity appears to improve memory performance specifically in aging mice. EC-SOD mimetic treatment during the course of aging may hold promise for aging-induced cognitive impairment.

Authors
Levin, ED; Christopher, NC; Crapo, JD
MLA Citation
Levin, ED, Christopher, NC, and Crapo, JD. "Memory decline of aging reduced by extracellular superoxide dismutase overexpression." Behav Genet 35.4 (July 2005): 447-453.
PMID
15971025
Source
pubmed
Published In
Behavior Genetics
Volume
35
Issue
4
Publish Date
2005
Start Page
447
End Page
453
DOI
10.1007/s10519-004-1510-y

Fetal nicotinic overload, blunted sympathetic responsivity, and obesity.

Authors
Levin, ED
MLA Citation
Levin, ED. "Fetal nicotinic overload, blunted sympathetic responsivity, and obesity." Birth Defects Res A Clin Mol Teratol 73.7 (July 2005): 481-484. (Review)
PMID
15959889
Source
pubmed
Published In
Birth Defects Research Part A: Clinical and Molecular Teratology
Volume
73
Issue
7
Publish Date
2005
Start Page
481
End Page
484
DOI
10.1002/bdra.20162

Reversal of clozapine effects on working memory in rats with fimbria-fornix lesions.

Clozapine is an effective antipsychotic drug, but its effects on cognitive function are unclear. Previously, we found that clozapine caused a working memory deficit, which was reversed by nicotine. Hippocampal systems are important in determining clozapine effect on memory. In the current study, the memory effects of clozapine and nicotine administration were determined in rats with lesions of the fimbria-fornix, a fiber bundle which carries cholinergic and other projections between the septum and the hippocampus. Female Sprague-Dawley rats were trained on a win-shift procedure in the radial-arm maze, in which each arm entry was rewarded once per session. Then, 13 rats received bilateral knife-cut lesions of the fimbria-fornix, while 14 rats underwent sham surgery. The rats were tested after subcutaneous injections with combinations of clozapine (0 and 1.25 mg/kg) and nicotine (0, 0.2, and 0.4 mg/kg). In sham-operated rats, clozapine caused a significant (P<0.005) working memory impairment. Fimbria-fornix lesions also caused a significant (P<0.05) memory impairment. Interestingly, clozapine had the opposite effect on working memory in the lesioned vs sham-operated rats. In contrast to its effects in controls, clozapine (1.25 mg/kg) significantly (P<0.05) attenuated the working memory deficit caused by fimbria-fornix lesions. Nicotine (0.2 mg/kg) did not quite significantly improve memory in lesioned rats. The effects of clozapine and nicotine were not additive in the lesioned rats. This study demonstrates the efficacy of clozapine in improving working memory in fimbria-fornix-lesioned rats, whereas it causes impairments in intact rats. Therapeutic treatment with clozapine in people with malfunctions of the hippocampus such as seen in schizophrenia may improve cognitive performance, whereas the same doses of clozapine may impair memory in individuals without hippocampal malfunction.

Authors
Addy, NA; Pocivavsek, A; Levin, ED
MLA Citation
Addy, NA, Pocivavsek, A, and Levin, ED. "Reversal of clozapine effects on working memory in rats with fimbria-fornix lesions." Neuropsychopharmacology 30.6 (June 2005): 1121-1127.
PMID
15688087
Source
pubmed
Published In
Neuropsychopharmacology (Nature)
Volume
30
Issue
6
Publish Date
2005
Start Page
1121
End Page
1127
DOI
10.1038/sj.npp.1300669

Nicotinic-serotonergic drug interactions and attentional performance in rats.

RATIONALE: Both central serotonergic and nicotinic systems play important roles in a variety of neurobehavioral functions; however, the interactions of these two systems have not been fully characterized. The current study served to determine the impact of a relatively selective 5-HT2A receptor antagonist, ketanserin, on attentional function in rats and the interactions of ketanserin with nicotine administration. METHODS: A standard operant visual signal detection task was used to assess sustained attention. In expt 1, adult female Sprague-Dawley rats (n = 39) were injected subcutaneously (SC) with a dose range of ketanserin (0, 0.25, 0.5 and 1 mg/kg). In expt 2, the interactions of acute ketanserin (0, 1 and 2 mg/kg, SC) and acute nicotine (0, 25 and 50 microg/kg, SC) were assessed. In expt 3, the interaction of acute ketanserin (0, 1 and 2 mg/kg, SC) and chronic nicotine (5 mg/kg per day, SC for 4 weeks via osmotic pump) was characterized. Using an operant visual signal detection task, three possible outcomes (dependent variables) were measured in each trial: percent hit, percent correct rejection, and response omissions. RESULTS: Ketanserin, when given alone, did not have a significant effect on either percent hit or percent correct rejection. Acute administration of 25 microg/kg nicotine significantly improved percent hit (i.e. improvement in choice accuracy), an effect that was reversed by acute administration of 1 mg/kg ketanserin. Chronic nicotine infusion for 28 consecutive days significantly increased percent correct rejection (i.e. improvement in choice accuracy) without development of tolerance, an effect which was reversed by an acute dose of 2 mg/kg ketanserin. CONCLUSIONS: These data suggest a functional interaction between nicotine and 5-HT2A receptor antagonist ketanserin.

Authors
Rezvani, AH; Caldwell, DP; Levin, ED
MLA Citation
Rezvani, AH, Caldwell, DP, and Levin, ED. "Nicotinic-serotonergic drug interactions and attentional performance in rats." Psychopharmacology (Berl) 179.3 (May 2005): 521-528.
PMID
15682310
Source
pubmed
Published In
Psychopharmacology
Volume
179
Issue
3
Publish Date
2005
Start Page
521
End Page
528
DOI
10.1007/s00213-004-2060-y

Nicotine and clozapine actions on pre-pulse inhibition deficits caused by N-methyl-D-aspartate (NMDA) glutamatergic receptor blockade.

Pre-pulse inhibition (PPI) is a phenomenon of neurobehavioral plasticity in which the motor response to a startling stimulus is inhibited by a preceding stimulus of a lower intensity. Most often this is tested in the auditory mode. PPI is impaired in a variety of clinical states, most notably schizophrenia. PPI is easily modeled in experimental animals and serves as a useful basis for determining the neural bases for behavioral plasticity. In the current study we examined the interactions of N-methyl-D-aspartate (NMDA) glutamate and nicotinic cholinergic receptor systems in the expression of PPI. Female Sprague-Dawley rats were tested for auditory PPI after s.c. injections of the NMDA antagonist dizocilpine (also known as MK-801), the prototypic nicotinic agonist nicotine or both. Vehicle (saline) injections served as the control. Nicotine (0.2-0.8 mg/kg) by itself caused a modest but significant dose-related improvement in PPI. Dizocilpine (25-100 microg/kg) caused a dramatic dose-related impairment in PPI. Interestingly, the low to moderate doses of nicotine potentiated the PPI impairment by dizocilpine. In a second experiment nicotine and dizocilpine interactions with the atypical antipsychotic drug clozapine were assessed. As in the first experiment, nicotine potentiated the adverse effects of dizocilpine on PPI. The combination of nicotine with clozapine effectively attenuated the PPI impairment caused by dizocilpine when neither alone was effective. Inasmuch as PPI is impaired in schizophrenia, its reversal by the antipsychotic drug clozapine may depend on co-administration of nicotine by smoking in the patients. Development of nicotinic-based co-treatments for schizophrenia may achieve this benefit of nicotine without the hazards of smoking. Sensory modulation deficit, which is a syndrome of sensory over-responsiveness may also benefit from such combination therapy.

Authors
Levin, ED; Petro, A; Caldwell, DP
MLA Citation
Levin, ED, Petro, A, and Caldwell, DP. "Nicotine and clozapine actions on pre-pulse inhibition deficits caused by N-methyl-D-aspartate (NMDA) glutamatergic receptor blockade." Prog Neuropsychopharmacol Biol Psychiatry 29.4 (May 2005): 581-586.
PMID
15866361
Source
pubmed
Published In
Progress in Neuro-Psychopharmacology & Biological Psychiatry
Volume
29
Issue
4
Publish Date
2005
Start Page
581
End Page
586
DOI
10.1016/j.pnpbp.2005.01.012

Olanzapine interactions with nicotine and mecamylamine in rats: effects on memory function.

Olanzapine is a widely used atypical antipsychotic drug. It is quite effective in reducing psychotic symptoms. However, the syndrome of schizophrenia encompasses more than psychosis. There is a pronounced cognitive impairment among other negative neurobehavioral symptoms. Classic antipsychotic drugs such as haloperidol do not alleviate cognitive impairment associated with schizophrenia and have been shown to exacerbate the dysfunction. The atypical antipsychotic drugs have a different profile of receptor actions and may have a different array of actions on cognitive function. The purpose of the current studies was to determine the effects of olanzapine on working memory function as measured by choice accuracy in the radial-arm maze. In determining the cognitive effects of any antipsychotic drug it is critical to determine its interactions with nicotinic manipulations since the great majority of people with schizophrenia smoke cigarettes and alterations in nicotinic receptors have been found in people with schizophrenia. Olanzapine caused a significant working memory impairment. Nicotine attenuated olanzapine-induced memory deficits. It may be the case that nicotinic co-treatment will be useful in addressing the cognitive impairment of schizophrenia.

Authors
Levin, ED; Petro, A; Beatty, A
MLA Citation
Levin, ED, Petro, A, and Beatty, A. "Olanzapine interactions with nicotine and mecamylamine in rats: effects on memory function." Neurotoxicol Teratol 27.3 (May 2005): 459-464.
PMID
15939205
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
27
Issue
3
Publish Date
2005
Start Page
459
End Page
464
DOI
10.1016/j.ntt.2005.01.011

Developmental exposure of rats to chlorpyrifos leads to behavioral alterations in adulthood, involving serotonergic mechanisms and resembling animal models of depression.

Developmental exposure to chlorpyrifos (CPF) causes persistent changes in serotonergic (5HT) systems. We administered 1 mg/kg/day CPF to rats on postnatal days 1-4, a regimen below the threshold for systemic toxicity. When tested in adulthood, CPF-exposed animals showed abnormalities in behavioral tests that involve 5HT mechanisms. In the elevated plus maze, males treated with CPF spent more time in the open arms, an effect seen with 5HT deficiencies in animal models of depression. Similarly, in an anhedonia test, the CPF-exposed group showed a decreased preference for chocolate milk versus water. Developmental CPF exposure also has lasting effects on cognitive function. We replicated our earlier finding that developmental CPF exposure ablates the normal sex differences in 16-arm radial maze learning and memory: during acquisition training, control male rats typically perform more accurately than do control females, but CPF treatment eliminated this normal sex difference. Females exposed to CPF showed a reduction in working and reference memory errors down to the rate of control males. Conversely, CPF-exposed males exhibited an increase in working and reference memory errors. After radial-arm acquisition training, we assessed the role of 5HT by challenging the animals with the 5HT2 receptor antagonist ketanserin. Ketanserin did not affect performance in controls but elicited dose-dependent increases in working and reference memory errors in the CPF group, indicating an abnormal dependence on 5HT systems. Our results indicate that neonatal CPF exposures, classically thought to be subtoxic, produce lasting changes in 5HT-related behaviors that resemble animal models of depression.

Authors
Aldridge, JE; Levin, ED; Seidler, FJ; Slotkin, TA
MLA Citation
Aldridge, JE, Levin, ED, Seidler, FJ, and Slotkin, TA. "Developmental exposure of rats to chlorpyrifos leads to behavioral alterations in adulthood, involving serotonergic mechanisms and resembling animal models of depression." Environ Health Perspect 113.5 (May 2005): 527-531.
PMID
15866758
Source
pubmed
Published In
Environmental health perspectives
Volume
113
Issue
5
Publish Date
2005
Start Page
527
End Page
531

Chronic nicotine and dizocilpine effects on regionally specific nicotinic and NMDA glutamate receptor binding.

Chronic nicotine administration has long been known to increase the number of high-affinity alpha4beta2 nicotinic receptors with lesser effects on low-affinity alpha7 nicotinic receptors. Nicotine has been shown to promote the release of a variety of neurotransmitters including glutamate. Nicotine may also interact directly with the glutamatergic receptors. Nicotinic-glutamate interactions may be critical to the long-term effects of nicotine. Conversely, glutamatergic drugs may interact with the nicotinic system. Such interactions have important implications in interpretation of the mechanism of drug actions, especially when the drugs are given together. The current study examined the effects of chronic administration of nicotine (5 mg of the nicotine base/kg/day for 28 days), dizocilpine (MK-801) (0.3 mg/kg/day for 28 days), an NMDA receptor antagonist, as well as the combination of the two drugs on nicotinic and NMDA receptor densities in discrete brain regions. The chronic dose of dizocilpine used was behaviorally active causing a dramatic reduction in prepulse inhibition (PPI) of acoustic startle response. The nicotine dose used did not significantly affect PPI but previously we have found it to be behaviorally active in improving working memory function. High-affinity nicotinic receptor binding, as has been seen previously, was significantly increased by chronic nicotine in most areas. Chronic dizocilpine alone did not affect high-affinity nicotinic receptor binding, but it did modify the effects of chronic nicotine, attenuating nicotine-induced increases in the frontal cortex and striatum. Low-affinity nicotinic binding was significantly increased by chronic nicotine in only one area, the cerebellum. Chronic dizocilpine significantly increased low-affinity nicotinic binding in several brain areas, the colliculi, hippocampus, and the hypothalamus. The combination of nicotine and dizocilpine attenuated the effects of each with diminished nicotine-induced increased nicotinic low-affinity binding in the cerebellum and diminished dizocilpine-induced increased nicotinic low-affinity binding in the hippocampus and hypothalamus. In contrast, chronic nicotine and dizocilpine had a mutually potentiating effect of increasing nicotinic low-affinity binding in the frontal cortex. NMDA receptor binding was affected only in the hippocampus, where both dizocilpine and nicotine significantly increased binding. Chronic nicotine effects on receptor regulation are significantly affected by concurrent blockade of NMDA glutamate receptors.

Authors
Levin, ED; Tizabi, Y; Rezvani, AH; Caldwell, DP; Petro, A; Getachew, B
MLA Citation
Levin, ED, Tizabi, Y, Rezvani, AH, Caldwell, DP, Petro, A, and Getachew, B. "Chronic nicotine and dizocilpine effects on regionally specific nicotinic and NMDA glutamate receptor binding." Brain Res 1041.2 (April 18, 2005): 132-142.
PMID
15829222
Source
pubmed
Published In
Brain Research
Volume
1041
Issue
2
Publish Date
2005
Start Page
132
End Page
142
DOI
10.1016/j.brainres.2005.01.104

Extracellular superoxide dismutase (EC-SOD) quenches free radicals and attenuates age-related cognitive decline: opportunities for novel drug development in aging.

Superoxide dismutase (SOD) is one of the most effective mechanisms in physiology for inactivating reactive oxygen species. Elevated SOD activity can be therapeutically useful by protecting against oxidative stress-induced neurotoxicity. Acutely increased extracellular-SOD (EC-SOD) activity protects against neurobehavioral impairment caused by acute ischemia. Chronically increased EC-SOD activity may also be therapeutically useful by protecting against chronic oxidative stress-induced neurobehavioral damage that accumulates during the aging process. We have found that mice with genetic overexpression of EC-SOD do not show the aging-induced decline in learning and memory that control, wild type mice show. From 14-22 months of age, the EC-SOD overexpressing mice have significantly better spatial learning working memory function than that of controls. This effect is specific to the aging period. Young adult EC-SOD overexpressing mice do not have better learning and memory function than controls. The beneficial effects of increased EC-SOD activity with aging may be achieved without risk of impairment during younger ages by chronically administering EC-SOD mimetics from mature adulthood into the aging period. Novel EC-SOD mimetics may be useful in attenuating aging-induced cognitive impairments and other aspects of physiological decline with aging.

Authors
Levin, ED
MLA Citation
Levin, ED. "Extracellular superoxide dismutase (EC-SOD) quenches free radicals and attenuates age-related cognitive decline: opportunities for novel drug development in aging." Curr Alzheimer Res 2.2 (April 2005): 191-196. (Review)
PMID
15974918
Source
pubmed
Published In
Current Alzheimer research
Volume
2
Issue
2
Publish Date
2005
Start Page
191
End Page
196

Ketanserin attenuates nicotine-induced working memory improvement in rats

Nicotinic systems have been shown in numerous studies to be important for spatial working memory. Nicotinic systems are certainly not acting alone in the basis of memory function, but act in concert with a variety of other neural systems. Important for these interactions is nicotinic induced release of a variety of neurotransmitters involved in memory function including serotonin (5-HT). We have found that the 5-HT2 receptor antagonist, ketanserin, effectively attenuated nicotine-induced attentional improvement. The current study explored the interaction between nicotinic and serotonergic systems in the performance of a spatial working memory task in the radial-arm maze. Female Sprague-Dawley rats were trained on the win-shift working memory task on the 8-arm radial maze. After 18 sessions of acquisition training the rats were given acute doses of nicotine (0.2 and 0.4 mg/kg), ketanserin (0.5, 1 and 2 mg/kg) or combinations of the two. The vehicle served as the control. As seen in previous studies, nicotine caused a significant improvement in working memory performance as indexed by the number of correct arm entries before the first error (entries to repeat). Ketanserin at the doses tested did not cause a significant effect on choice accuracy, but it did significantly attenuate the improvement caused by the 0.2 mg/kg nicotine dose. The higher 0.4 mg/kg nicotine dose was nearly sufficient to overcome the ketanserin effect. This study shows that, as with attentional function, nicotine-induced working memory improvement is attenuated by the 5-HT2 antagonist ketanserin. Given that many antipsychotic drugs have substantial 5-HT2 antagonist effects, these atypical antipsychotic drugs may reduce the cognitive improvements caused by nicotinic treatments. © 2005 Elsevier Inc. All rights reserved.

Authors
Levin, E; Icenogle, L; Farzad, A
MLA Citation
Levin, E, Icenogle, L, and Farzad, A. "Ketanserin attenuates nicotine-induced working memory improvement in rats." Pharmacology Biochemistry and Behavior 82.2 (2005): 289-292.
PMID
16185760
Source
scival
Published In
Pharmacology Biochemistry and Behavior
Volume
82
Issue
2
Publish Date
2005
Start Page
289
End Page
292
DOI
10.1016/j.pbb.2005.08.017

Marine and freshwater toxin impacts on neurobehavioral function

Authors
Levin, ED
MLA Citation
Levin, ED. "Marine and freshwater toxin impacts on neurobehavioral function." Neurotoxicology and Teratology 27.5 (2005): 693--.
Source
scival
Published In
Neurotoxicology and Teratology
Volume
27
Issue
5
Publish Date
2005
Start Page
693-
DOI
10.1016/j.ntt.2005.06.011

Developmental origins and environmental influences - Introduction

Authors
Heindel, JJ; Levin, E
MLA Citation
Heindel, JJ, and Levin, E. "Developmental origins and environmental influences - Introduction." Birth Defects Research Part A - Clinical and Molecular Teratology 73.7 (2005): 469--.
PMID
15959884
Source
scival
Published In
Birth Defects Research Part A - Clinical and Molecular Teratology
Volume
73
Issue
7
Publish Date
2005
Start Page
469-
DOI
10.1002/bdra.20141

Nicotinic involvement in memory function in zebrafish.

Zebrafish are an emerging model for the study of the molecular mechanisms of brain function. To conduct studies of the neural bases of behavior in zebrafish, we must understand the behavioral function of zebrafish and how it is altered by perturbations of brain function. This study determined nicotine actions on memory function in zebrafish. With the methods that we have developed to assess memory in zebrafish using delayed spatial alternation (DSA), we determined the dose effect function of acute nicotine on memory function in zebrafish. As in rodents and primates, low nicotine doses improve memory in zebrafish, while high nicotine doses have diminished effect and can impair memory. This study shows that nicotine affects memory function in zebrafish much like in rats, mice, monkeys and humans. Now, zebrafish can be used to help understand the molecular mechanisms crucial to nicotine effects on memory.

Authors
Levin, ED; Chen, E
MLA Citation
Levin, ED, and Chen, E. "Nicotinic involvement in memory function in zebrafish." Neurotoxicol Teratol 26.6 (November 2004): 731-735.
PMID
15451037
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
26
Issue
6
Publish Date
2004
Start Page
731
End Page
735
DOI
10.1016/j.ntt.2004.06.010

The use of zebrafish (Danio rerio) as a model system in neurobehavioral toxicology.

Authors
Scalzo, FM; Levin, ED
MLA Citation
Scalzo, FM, and Levin, ED. "The use of zebrafish (Danio rerio) as a model system in neurobehavioral toxicology." Neurotoxicol Teratol 26.6 (November 2004): 707-708.
PMID
15451033
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
26
Issue
6
Publish Date
2004
Start Page
707
End Page
708
DOI
10.1016/j.ntt.2004.06.008

Developmental chlorpyrifos effects on hatchling zebrafish swimming behavior.

Chlorpyrifos (CPF), a widely used organophosphate insecticide and potent acetylcholinesterase inhibitor, interferes with neurobehavioral development. Rat models have been key in demonstrating that developmental CPF exposure causes learning deficits and locomotor activity alterations, which persist into adulthood. Complementary nonmammalian models can be useful in determining the neurodevelopmental mechanisms underlying these persisting behavioral effects. Zebrafish (Danio rerio) with their clear chorion and extensive developmental information base provide an excellent model for assessment of molecular processes of toxicant-impacted neurodevelopment. We have developed methods for assessing spatial discrimination learning in adult zebrafish and have documented persisting effects of developmental CPF exposure on swimming activity and learning after low and high doses of CPF (10 and 100 ng/ml) administered to zebrafish embryos on Days 1-5 postfertilization (pf). In the current study, we developed methods for behavioral assessment of CPF exposure on swimming activity in newly hatched zebrafish. An equal area segmented annular grid (concentric circles divided into quadrants through the diameter) was made in a 16-mm diameter cylinder. The test area was placed on a heating device secured to an Olympus SZH10 dissecting scope stage. Zebrafish embryos were exposed to 10 ng/ml CPF, 100 ng/ml CPF, or vehicle control (25 microl/ml DMSO) (n=8-10/treatment group). Each treatment group was kept in a total volume of 25 ml of egg water (60 mg/ml Instant Ocean) including DMSO with or without CPF mixed to above dilutions in an incubator set at 28.5 degrees C. CPF dilutions or vehicle were changed daily with exposure ending on Day 5 pf. Testing of larval zebrafish was performed on Days 6 and 9 pf. The fish were placed in the test cylinder with 1.5 ml of egg H(2)O (28.5 degrees C). After a 2-min acclimation period, the swimming activity of the fish was measured for a 3-min testing session. The 100 ng/ml CPF dose caused significant slowing of swimming activity on Days 6 and 9 pf and had persisting effects of impairing spatial discrimination and decreasing response latency in adulthood. Developmental exposure to 10 ng/ml of CPF did not cause a significant change in locomotor activity during the period soon after hatching. CPF exposure during early development caused clear behavioral impairments detectable during the posthatching period. In a previous study, we found that early developmental CPF exposure caused behavioral alterations in zebrafish, which lasted throughout adulthood. The molecular mechanisms by which early developmental CPF exposure produces these behavioral impairments expressed in adulthood can now be studied in the zebrafish model.

Authors
Levin, ED; Swain, HA; Donerly, S; Linney, E
MLA Citation
Levin, ED, Swain, HA, Donerly, S, and Linney, E. "Developmental chlorpyrifos effects on hatchling zebrafish swimming behavior." Neurotoxicol Teratol 26.6 (November 2004): 719-723.
PMID
15451035
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
26
Issue
6
Publish Date
2004
Start Page
719
End Page
723
DOI
10.1016/j.ntt.2004.06.013

Baclofen interactions with nicotine in rats: effects on memory.

Nicotine has been shown in numerous previous studies to significantly improve memory on the radial-arm maze, yet the critical mechanisms underlying this effect are not fully characterized. Nicotine stimulates the release of a number of neurotransmitters important for memory function including (gamma-aminobutyric acid) GABA. The importance of nicotinic-GABA interactions regarding memory is currently unknown. The purpose of the current study was to determine the interactive effects of nicotine and the GABA agonist baclofen on working memory function as measured by choice accuracy in the radial-arm maze. Female Sprague-Dawley rats trained to asymptotic performance levels on a win-shift eight-arm radial maze task were used for assessment of nicotine-baclofen interactions. Low doses of baclofen improved memory performance while higher doses impaired it. Nicotine, as seen before, improved memory performance. Nicotine also significantly reversed the higher dose baclofen-induced deficit. These data show the importance of both nicotinic and GABA systems in working memory function and the interactions between these two transmitter receptor systems. This not only provides information concerning the neural bases of cognitive performance, it also lends insight into new combination treatments for memory impairment.

Authors
Levin, ED; Weber, E; Icenogle, L
MLA Citation
Levin, ED, Weber, E, and Icenogle, L. "Baclofen interactions with nicotine in rats: effects on memory." Pharmacol Biochem Behav 79.2 (October 2004): 343-348.
PMID
15501311
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
79
Issue
2
Publish Date
2004
Start Page
343
End Page
348
DOI
10.1016/j.pbb.2004.08.013

Adolescent and adult rats respond differently to nicotine and alcohol: motor activity and body temperature.

Alcohol and nicotine are the most widely abused drugs in the world. The use of these addictive drugs often begins in adolescence, however, little is known about the different impacts of nicotine and alcohol on adolescents versus adults. This study examined both the individual and combined effects of nicotine and alcohol on body temperature and locomotor activity in adolescent and adults rats. Rats were injected with saline (SC) + saline (IP), nicotine (SC) + saline (IP), alcohol (IP) + saline (SC) or alcohol (IP) + nicotine (SC). The dose selected for nicotine was 0.2 mg/kg and for alcohol 2.5 g/kg (16% v/v). For each age/treatment, 10-13 animals were used, with each animal receiving only one treatment. In regards to body temperature, both nicotine and alcohol caused a significant age x drug interaction. The combination of nicotine and alcohol caused greater drop in body temperature in adolescent than in adult rats. Neither of the two drugs, when given alone, caused differential effects in adolescents or adult rats, though both resulted in drop in body temperature. In terms of locomotor activity, the treatment that produced a significantly different effect between adolescents and adults was nicotine alone. Nicotine significantly decreased locomotor activity in adolescent compared to adult rats. These preliminary results suggest that adolescent rats may have an increased sensitivity to nicotine and alcohol, which may consequently impact their initial addiction to these two drugs.

Authors
Rezvani, AH; Levin, ED
MLA Citation
Rezvani, AH, and Levin, ED. "Adolescent and adult rats respond differently to nicotine and alcohol: motor activity and body temperature." Int J Dev Neurosci 22.5-6 (August 2004): 349-354.
PMID
15380834
Source
pubmed
Published In
International Journal of Developmental Neuroscience
Volume
22
Issue
5-6
Publish Date
2004
Start Page
349
End Page
354
DOI
10.1016/j.ijdevneu.2004.03.007

Adolescent rats show differential effects of nicotine and alcohol relative to adults.

Authors
Levin, ED; Rezvani, AH
MLA Citation
Levin, ED, and Rezvani, AH. "Adolescent rats show differential effects of nicotine and alcohol relative to adults." May 2004.
Source
wos-lite
Published In
Alcoholism: Clinical and Experimental Research
Volume
28
Issue
5
Publish Date
2004
Start Page
175A
End Page
175A

Nicotinic receptor modulation of attention: An endophenotype for therapeutic drug development

Authors
Weiser, M; Levin, ED; George, TP; Newhouse, PA; Leonard, S
MLA Citation
Weiser, M, Levin, ED, George, TP, Newhouse, PA, and Leonard, S. "Nicotinic receptor modulation of attention: An endophenotype for therapeutic drug development." April 15, 2004.
Source
wos-lite
Published In
Biological Psychiatry
Volume
55
Publish Date
2004
Start Page
152S
End Page
152S

Nicotine-antipsychotic drug interactions and attentional performance in female rats (vol 486, pg 175, 2004)

Authors
Rezvani, AH; Levin, ED
MLA Citation
Rezvani, AH, and Levin, ED. "Nicotine-antipsychotic drug interactions and attentional performance in female rats (vol 486, pg 175, 2004)." EUROPEAN JOURNAL OF PHARMACOLOGY 489.3 (April 12, 2004): 215-215.
Source
wos-lite
Published In
European Journal of Pharmacology
Volume
489
Issue
3
Publish Date
2004
Start Page
215
End Page
215
DOI
10.1016/j.ejphar.2003.03.009

Nicotine-antipsychotic drug interactions and attentional performance in female rats.

Schizophrenia is marked by pronounced cognitive impairments in addition to the hallmark psychotic symptoms like hallucinations. Antipsychotic drugs can effectively reduce these hallucinations; however, the drugs have not resolved the cognitive impairment. Interestingly, nicotine, a drug commonly self-administered by people with schizophrenia, has been shown to significantly improve cognitive function of people with schizophrenia. The current study was conducted to determine the effect of typical (haloperidol) and atypical (clozapine and risperidone) antipsychotic drug treatment on sustained attention in rats performing a visual signal detection task. In addition, the interaction of haloperidol with chronic nicotine administration was assessed. Female Sprague-Dawley rats were injected subcutaneously with clozapine (0, 0.6, 1.25 and 2.5 mg/kg), risperidone (0, 0.025, 0.05 and 0.1 mg/kg) or haloperidol (0, 0.01, 0.02 and 0.04 mg/kg). In the second part of the study, the interaction of acute haloperidol (0, 0.005, 0.01 and 0.02 mg/kg) and chronic nicotine (5 mg/kg/day, for 4 weeks via osmotic minipump) was characterized. Clozapine, risperidone and haloperidol all caused dose-related impairments in percent hit performance. There was a significant linear dose-related impairment in percent hit caused by risperidone. All the doses of clozapine caused a significant impairment in percent hit at the higher luminance intensities in the visual signal detection task. The 0.01 and 0.02 mg/kg haloperidol doses caused significant decreases in percent hit. The 0.04 mg/kg haloperidol dose impaired performance of the task to the point that reliable choice accuracy measurements could not be made. Chronic nicotine infusion significantly diminished the impairing effects of haloperidol on performance during weeks 1-2. In summary, both typical and atypical antipsychotic drugs significantly impaired sustained attention in rats. Haloperidol was more detrimental than clozapine and risperidone. Chronic nicotine diminished the adverse effects of haloperidol on performance. This study establishes a paradigm to reliably determine the attentional impairment caused by antipsychotic drugs.

Authors
Rezvani, AH; Levin, ED
MLA Citation
Rezvani, AH, and Levin, ED. "Nicotine-antipsychotic drug interactions and attentional performance in female rats." Eur J Pharmacol 486.2 (February 20, 2004): 175-182.
PMID
14975706
Source
pubmed
Published In
European Journal of Pharmacology
Volume
486
Issue
2
Publish Date
2004
Start Page
175
End Page
182
DOI
10.1016/j.ejphar.2003.12.021

Chronic transdermal nicotine patch treatment effects on cognitive performance in age-associated memory impairment.

OBJECTIVES: Chronic transdermal nicotine has been found to improve attentional performance in patients with Alzheimer's disease (AD), but little is known about chronic nicotine effects in age-associated memory impairment (AAMI), a milder form of cognitive dysfunction. The current study was performed to determine the clinical and neuropsychological effects of chronic transdermal nicotine in AAMI subjects over a 4-week period. DESIGN: The double-blind, placebo-controlled, cross-over study consisted of two 4-week periods separated by a 2-week washout period. SETTING: An outpatient setting was used. PARTICIPANTS: The subjects ( n=11) met criteria for AAMI. INTERVENTIONS: The subjects were given nicotine patches (Nicotrol) to wear for 16 h a day at the following doses: 5 mg/day during week 1, 10 mg/day during week 2 and week 3 and 5 mg/day during week 4. MEASUREMENTS: The effects of nicotine treatment were determined with the clinical global impressions questionnaire, Conners' Continuous Performance test, and the automated neuropsychologic assessment metrics (ANAM) computerized neuropsychology battery. RESULTS: Nicotine significantly improved the clinical global impression score as assessed by participants, as well as objective tests of attentional function on the Connors' Continuous Performance Test and decision reaction time on the neuropsychology test battery. Nicotine did not improve performance on other tests measuring motor and memory function. CONCLUSION: Chronic transdermal nicotine treatment in AAMI subjects caused a sustained improvement in clinical symptoms and objective computerized tests of attention. These results support the further investigation of nicotinic treatment as a promising therapy for AAMI.

Authors
White, HK; Levin, ED
MLA Citation
White, HK, and Levin, ED. "Chronic transdermal nicotine patch treatment effects on cognitive performance in age-associated memory impairment." Psychopharmacology (Berl) 171.4 (February 2004): 465-471.
PMID
14534771
Source
pubmed
Published In
Psychopharmacology
Volume
171
Issue
4
Publish Date
2004
Start Page
465
End Page
471
DOI
10.1007/s00213-003-1614-8

Neurobehavioral assessment of mice after developmental AZT exposure.

Azidothymidine (AZT) is administered to pregnant women with HIV to prevent the spread of infection to their fetuses. Since gestation is a period of critical neurodevelopment, it is important to determine the risk AZT exposure may pose to neurobehavioral function of the offspring. The current study focused on teratological risks of developmental AZT exposure to neurocognitive function. Male and female Swiss mice were administered AZT or vehicle (0, 100, or 200 mg/kg/day po given twice daily in equal amounts for 32 weeks before and during gestation). Adult male and female offspring (n = 10/sex/treatment group) underwent neurobehavioral testing focused on determining learning and memory capabilities in the radial-arm maze. AZT exposure did not cause significant deficits during radial-arm maze acquisition. No impairment was seen in asymptotic levels of choice accuracy indicative of working memory function. Attempts to unmask subtle learning impairments following developmental AZT by the introduction of behavioral challenges such as reduction of motivational state (food restriction either 4-6 h or 22-24 h) or imposition of intrasession delays of 1.5 min to 2.5 h were unsuccessful. With a 4-week intersession delay, a significant AZT Treatment x Delay effect was seen with a significantly greater decline seen in the controls as compared to the 100 mg/kg/day AZT group. Locomotor activity on the radial-arm maze was significantly affected by AZT treatment (100 mg/kg/day) during the acquisition phase, but not during the other test phases. No behavioral alterations were seen related to stress as measured by the elevated plus maze. Vestibulomotor functioning on the balance beam remained unaltered. Using an extended dosing regimen including dosing of both sires and dams, as well as placing a greater demand on reproductive system performance with three continuous breedings, this study detected only subtle neurobehavioral impairments in mice after prenatal AZT exposure at clinically relevant doses.

Authors
Levin, ED; Brunssen, S; Wolfe, GW; Harry, GJ
MLA Citation
Levin, ED, Brunssen, S, Wolfe, GW, and Harry, GJ. "Neurobehavioral assessment of mice after developmental AZT exposure." Neurotoxicol Teratol 26.1 (January 2004): 65-71.
PMID
15001215
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
26
Issue
1
Publish Date
2004
Start Page
65
End Page
71
DOI
10.1016/j.ntt.2003.10.001

Behavioral alterations in adolescent and adult rats caused by a brief subtoxic exposure to chlorpyrifos during neurulation.

The widely used organophosphate insecticide, chlorpyrifos (CPF), elicits neurobehavioral abnormalities after apparently subtoxic neonatal exposures. In the current study, we administered 1 or 5 mg/kg/day of CPF to pregnant rats on gestational days 9-12, the embryonic phase spanning formation and closure of the neural tube. Although there were no effects on growth or viability, offspring showed behavioral abnormalities when tested in adolescence and adulthood. In the CPF-exposed groups, locomotor hyperactivity was noted in early T-maze trials, and in the elevated plus-maze; alterations in the rate of habituation were also identified. Learning and memory were adversely affected, as assessed using the 16-arm radial maze. Although all CPF-exposed animals eventually learned the task, reference and working memory were impaired in the early training sessions. After training, rats in the CPF group did not show the characteristic amnestic effect of scopolamine, a muscarinic acetylcholine antagonist, suggesting that, unlike the situation in the control group, muscarinic pathways were not used to solve the maze. These results indicate that apparently subtoxic CPF exposure during neurulation adversely affects brain development, leading to behavioral anomalies that selectively include impairment of cholinergic circuits used in learning and memory. The resemblance of these findings to those of late gestational or neonatal CPF exposure indicates a prolonged window of vulnerability of brain development to CPF.

Authors
Icenogle, LM; Christopher, NC; Blackwelder, WP; Caldwell, DP; Qiao, D; Seidler, FJ; Slotkin, TA; Levin, ED
MLA Citation
Icenogle, LM, Christopher, NC, Blackwelder, WP, Caldwell, DP, Qiao, D, Seidler, FJ, Slotkin, TA, and Levin, ED. "Behavioral alterations in adolescent and adult rats caused by a brief subtoxic exposure to chlorpyrifos during neurulation." Neurotoxicol Teratol 26.1 (January 2004): 95-101.
PMID
15001218
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
26
Issue
1
Publish Date
2004
Start Page
95
End Page
101
DOI
10.1016/j.ntt.2003.09.001

Erratum: Nicotine-antipsychotic drug interactions and attentional performance in female rats (European Journal of Pharmacology (2004) 486 (175-182) DOI: 10.1016/j.ejphar.2003.12.021.)

Authors
Rezvani, AH; Levin, ED
MLA Citation
Rezvani, AH, and Levin, ED. "Erratum: Nicotine-antipsychotic drug interactions and attentional performance in female rats (European Journal of Pharmacology (2004) 486 (175-182) DOI: 10.1016/j.ejphar.2003.12.021.)." European Journal of Pharmacology 489.3 (2004): 215--.
Source
scival
Published In
European Journal of Pharmacology
Volume
489
Issue
3
Publish Date
2004
Start Page
215-
DOI
10.1016/j.ejphar.2004.03.009

Heterogeneity of toxicant response: sources of human variability.

While risk assessment models attempt to predict human risk to toxicant exposure, in many cases these models cannot account for the wide variety of human responses. This review addresses several primary sources of heterogeneity that may affect individual responses to drug or toxicant exposure. Consideration was given to genetic polymorphisms, age-related factors during development and senescence, gender differences associated with hormonal function, and preexisting diseases influenced by toxicant exposure. These selected examples demonstrate the need for additional steps in risk assessment that are needed to more accurately predict human responses to toxicants and drugs.

Authors
Aldridge, JE; Gibbons, JA; Flaherty, MM; Kreider, ML; Romano, JA; Levin, ED
MLA Citation
Aldridge, JE, Gibbons, JA, Flaherty, MM, Kreider, ML, Romano, JA, and Levin, ED. "Heterogeneity of toxicant response: sources of human variability." Toxicol Sci 76.1 (November 2003): 3-20. (Review)
PMID
12883075
Source
pubmed
Published In
Toxicological Sciences (Elsevier)
Volume
76
Issue
1
Publish Date
2003
Start Page
3
End Page
20
DOI
10.1093/toxsci/kfg204

Ventral hippocampal NMDA blockade and nicotinic effects on memory function.

Nicotinic acetylcholine and NMDA glutamate receptors play critical roles in memory function. The brain areas involved in their interaction are still under investigation. One likely area is the hippocampus. Ventral hippocampal administration of nicotinic antagonists impair memory. Hippocampal administration of NMDA antagonists also cause memory impairments. We evaluated the importance of ventral hippocampal NMDA receptors for nicotinic actions on memory by testing the impact of systemic nicotine on memory with and without administration of the NMDA antagonist dizocilpine into the ventral hippocampus. Sprague-Dawley rats (N=11) trained on the 16-arm radial maze were bilaterally implanted with local infusion cannulae in the ventral hippocampus. The effects on memory function of ventral hippocampal infusions of 0, 2, 6 and 18 microg per side of dizocilpine were examined with and without acute systemic nicotine administration (0 or 0.4 mg/kg). The dizocilpine doses tested did not cause memory deficits by themselves but only did so when given in combination with systemic nicotine. Blocking NMDA ventral hippocampal actions revealed an impairing action of nicotine on memory. Nicotine effects on other non-NMDA hippocampal receptor systems or extra-hippocampal systems may have been left unchecked by the diminished nicotinic effect on ventral hippocampal NMDA receptors.

Authors
Levin, ED; Sledge, D; Baruah, A; Addy, NA
MLA Citation
Levin, ED, Sledge, D, Baruah, A, and Addy, NA. "Ventral hippocampal NMDA blockade and nicotinic effects on memory function." Brain Res Bull 61.5 (September 30, 2003): 489-495.
PMID
13679247
Source
pubmed
Published In
Brain Research Bulletin
Volume
61
Issue
5
Publish Date
2003
Start Page
489
End Page
495

Adolescent-onset nicotine self-administration modeled in female rats.

RATIONALE: Although the great majority of tobacco addiction begins during adolescence, little is known about differential nicotine effects in adolescents versus adults. OBJECTIVES: A rat model was used to determine the impact of the age of onset on nicotine self-administration. METHODS: In expt 1, nicotine self-administration of female Sprague-Dawley rats over a range of acute doses (0.01-0.08 mg/kg per infusion) was determined in adolescent (beginning at 54-62 days) versus adult (beginning at 84-90 days). In expt 2, chronic nicotine self-administration over 4 weeks from adolescence into adulthood was compared with the chronic self-administration beginning in adulthood. In expt 3, adolescent-adult differences in nicotine effects on body temperature and locomotor responses were determined. RESULTS: Adolescent-onset rats showed a significant main effect of increased nicotine intake compared with adult-onset rats in an eight-fold range of acute unit doses/infusion. Significant age differences were also seen in the chronic level of nicotine self-administration. Over 4 weeks, the adolescent-onset group had nearly double the rate of nicotine self-administration of the benchmark nicotine dose (0.03 mg/kg per infusion) compared to the adult-onset group. This increased nicotine intake persisted into adulthood. Adolescent rats had significantly greater response than adults to the hypothermic effects of nicotine, but had significantly less response than adults to the reduction in locomotor activity seen after nicotine. CONCLUSIONS: Adolescent-onset nicotine self-administration in female rats was associated with significantly higher levels of nicotine self-administration versus rats, which began nicotine self-administration in adulthood. This greater self-administration persists into adulthood and may underlie greater propensity of adolescents to nicotine addiction.

Authors
Levin, ED; Rezvani, AH; Montoya, D; Rose, JE; Swartzwelder, HS
MLA Citation
Levin, ED, Rezvani, AH, Montoya, D, Rose, JE, and Swartzwelder, HS. "Adolescent-onset nicotine self-administration modeled in female rats." Psychopharmacology (Berl) 169.2 (September 2003): 141-149.
PMID
12764575
Source
pubmed
Published In
Psychopharmacology
Volume
169
Issue
2
Publish Date
2003
Start Page
141
End Page
149
DOI
10.1007/s00213-003-1486-y

Lobeline-induced learning improvement of rats in the radial-arm maze.

Lobeline is a nicotinic ligand with some nicotine-like effects, but with some atypical effects as well, including actions as a nicotinic antagonist. Lobeline, like nicotine, has been found to significantly improve memory function as well as provide anxiolytic-like effects in the elevated plus maze. Lobeline effects on learning remain to be fully characterized. Nicotine has been found to improve learning of shock avoidance tasks. Other nicotinic agonists also have been shown to improve learning performance. However, this effect is limited. In some tasks, nicotine has been found to cause deficits. In the current study, effects of lobeline and nicotine injections were assessed in a repeated acquisition procedure in the radial-arm maze for 3 weeks of drug administration. Lobeline (0.3 and 0.9 mg/kg) improved learning on the radial-arm maze. Neither nicotine dose (0.1 and 0.3 mg/kg) improved learning. This nicotine dose range was previously found to improve post-acquisition working memory performance in the radial-arm maze. The atypical effects of lobeline may underlie its greater efficacy than nicotine for improving repeated acquisition. The effect of lobeline improving learning may be useful in the development of novel treatments for learning deficits.

Authors
Levin, ED; Christopher, CN
MLA Citation
Levin, ED, and Christopher, CN. "Lobeline-induced learning improvement of rats in the radial-arm maze." Pharmacol Biochem Behav 76.1 (August 2003): 133-139.
PMID
13679226
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
76
Issue
1
Publish Date
2003
Start Page
133
End Page
139

Nicotine-alcohol interactions and attentional performance on an operant visual signal detection task in female rats.

Nicotine and alcohol are very often co-used and co-abused. Thus, it is important to understand their interactions. In many ways, nicotine and alcohol have opposing effects. This can be clearly seen in terms of their effects on cognitive function. Nicotine effectively improves attention while alcohol impairs it. The current study was conducted to determine in a rat model the interaction of nicotine and alcohol on attention using an operant visual signal detection task. It is hypothesized that nicotine would reverse the alcohol-induced impairment in accuracy of performance in this task. Female Sprague-Dawley rats (N=35) were trained on a visual operant signal detection task for food reinforcement with 300 trials/session in three equal time blocks. The rats were divided into poor and good performers according to their predrug baseline performance accuracy. The first experiment examined the dose-effect function of alcohol (0, 0.375, and 0.75 g/kg i.p.) on this task. The lower alcohol dose significantly impaired percent correct rejection in the high-performing rats but not the low-performing rats. The higher alcohol dose significantly impaired percent hit performance during the first two thirds of the session in both high- and low-performing groups. The second experiment examined alcohol (0.75 g/kg i.p.) interactions with nicotine (0, 12.5, 25, and 50 microg/kg s.c.) on attentional performance. The 25 and 50 microg/kg nicotine doses caused a significant (P<.05) improvement in hit accuracy. Alcohol blocked this nicotine-induced improvement, even though at this later time it no longer had an effect of its own. In the high baseline group, the 25 microg/kg nicotine dose also caused a significant (P<.025) improvement in hit accuracy. As in Experiment 1, the high baseline group was not significantly impaired by 0.75 g/kg of alcohol. However, this alcohol dose did eliminate the nicotine-induced improvement. These results suggest that alcohol, when given alone, impairs sustained attention and blocks nicotine-induced attentional improvements even when it does not cause impairments on its own.

Authors
Rezvani, AH; Levin, ED
MLA Citation
Rezvani, AH, and Levin, ED. "Nicotine-alcohol interactions and attentional performance on an operant visual signal detection task in female rats." Pharmacol Biochem Behav 76.1 (August 2003): 75-83.
PMID
13679219
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
76
Issue
1
Publish Date
2003
Start Page
75
End Page
83

NMDA systems in the amygdala and piriform cortex and nicotinic effects on memory function.

Both nicotinic cholinergic and NMDA glutaminergic systems are important for memory function. Nicotine has been found repeatedly to significantly improve working memory performance in the radial-arm maze. The NMDA antagonist dizocilpine has been found to impair working memory performance. There is neuropharmacological evidence that these two systems are functionally related. Nicotine is potent at releasing many transmitters including glutamate. The current study was conducted to examine the interaction of nicotinic and NMDA systems within the amygdala with regard to working and reference memory. Rats were trained on a working/reference procedure on a 16-arm radial maze. After acquisition, local infusion cannulae were implanted bilaterally into the amygdala and piriform cortex using stereotaxic techniques. Then 20 min prior to running the rats on the radial-arm maze, they were injected subcutaneously with (-) nicotine ditartrate at doses of 0 and 0.4 mg/kg. Following this, the rats received local infusions of (+) dizocilpine maleate (MK-801) at doses of 0, 2, 6 and 18 microg per side into the lateral amygdala or piriform cortex 10 min prior to running on the radial-arm maze. Each of the eight nicotine and dizocilpine combinations was administered to each rat in a counterbalanced order. After completion of the drug sessions the rats were sacrificed, and using histological methods the cannulae placements were verified. Acute amygdalar infusions of the NMDA glutamate receptor antagonist dizocilpine induced dose-related working and reference memory deficits in the radial-arm maze. Systemic nicotine was not seen to reverse these effects. Dizocilpine infusions into the adjacent piriform cortex did not impair memory function, supporting the specificity of dizocilpine effects in the amygdala. Latency effects were seen with both drugs in both areas. Latencies were decreased with both systemic nicotine and dizocilpine in both the lateral amygdala and the piriform cortex. This study demonstrated the importance of NMDA glutamate systems in the amygdala for appetitively-motivated spatial memory performance.

Authors
May-Simera, H; Levin, ED
MLA Citation
May-Simera, H, and Levin, ED. "NMDA systems in the amygdala and piriform cortex and nicotinic effects on memory function." Brain Res Cogn Brain Res 17.2 (July 2003): 475-483.
PMID
12880917
Source
pubmed
Published In
Cognitive Brain Research
Volume
17
Issue
2
Publish Date
2003
Start Page
475
End Page
483

Learning impairment caused by a toxin produced by Pfiesteria piscicida infused into the hippocampus of rats.

Pfiesteria piscicida, an estuarine dinoflagellate, which has been shown to kill fish, has also been associated with neurocognitive deficits in humans. With a rat model, we have demonstrated the cause-and-effect relationship between Pfiesteria exposure and learning impairment. In several studies, we have replicated the finding in Sprague-Dawley rats that exposure to fixed acute doses of Pfiesteria cells or filtrates caused radial-arm maze learning impairment. Recently, this finding of Pfiesteria-induced learning impairment in rats has been independently replicated in another laboratory as well. We have demonstrated significant Pfiesteria-induced learning impairment in both the win-shift and repeated-acquisition tasks in the radial-arm maze and in reversal learning in a visual operant signal detection task. These learning impairments have been seen as long as 10 weeks after a single acute exposure to Pfiesteria. In the current study, we used a hydrophilic toxin isolated from clonal P. piscicida cultures (PfTx) and tested its effect when applied locally to the ventral hippocampus on repeated acquisition of rats in the radial-arm maze. Toxin exposure impaired choice accuracy in the radial-arm maze repeated acquisition procedure. The PfTx-induced impairment was seen at the beginning of the session and the early learning deficit was persistent across 6 weeks of testing after a single administration of the toxin. Eventually, with enough practice, in each session, the PfTx-exposed rats did learn that session's problem as did control rats. This model has demonstrated the cause-and-effect relationship between exposure to a hydrophilic toxin produced by P. piscicida and learning impairment, and specifically that the ventral hippocampus was critically involved.

Authors
Levin, ED; Blackwelder, WP; Glasgow, HB; Burkholder, JM; Moeller, PDR; Ramsdell, JS
MLA Citation
Levin, ED, Blackwelder, WP, Glasgow, HB, Burkholder, JM, Moeller, PDR, and Ramsdell, JS. "Learning impairment caused by a toxin produced by Pfiesteria piscicida infused into the hippocampus of rats." Neurotoxicol Teratol 25.4 (July 2003): 419-426.
PMID
12798959
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
25
Issue
4
Publish Date
2003
Start Page
419
End Page
426

Nicotinic-glutamatergic interactions and attentional performance on an operant visual signal detection task in female rats.

Nicotinic systems have been shown to be critically involved in cognitive function including attention. Nicotine has been shown to improve performance on attentional tasks in humans with Alzheimer's disease, schizophrenia and attention deficit hyperactivity disorder. Nicotine has mixed effects on attentional accuracy in unimpaired rats with findings of increased, reduced or unaltered accuracy under different conditions. Nicotine effects on attentional function in rats might be more clearly seen in reversing impaired performance. The current study determined nicotine effects on attentional accuracy reduced by the NMDA receptor antagonist dizocilpine (MK-801). Sprague-Dawley rats (N=35) were trained on a food-motivated two-lever operant task with one lever correct after a brief visual signal (0.027-1.22 lx) for hits and the other lever correct after the absence of a signal for correct rejections. First, a dose response study of dizocilpine was conducted to determine the threshold for impairment. The rats were administered acute doses of dizocilpine (0, 12.5, 25 and 50 microg/kg, sc). The 50 microg/kg dose caused significant (p<0.0005) reduction in percent hit at the four highest signal intensities. Percent correct rejection was also significantly lowered by this dose (p<0.005). No effect was seen with 12.5 microg/kg and only minimal effect seen with 25 microg/kg. Then, nicotine-dizocilpine interactions were investigated. The rats were administered acute doses of dizocilpine (0, 37.5 and 50 microg/kg, sc) and nicotine (0, 25 and 50 microg/kg, sc), alone or in combination. Percent hit was affected by nicotine and dizocilpine in a complex fashion with only the nicotinexdizocilpinexsignal intensity interaction being significant (p<0.05). Percent correct rejection showed a more straightforward effect. Percent correct rejection was significantly reduced by 50 microg/kg dizocilpine (p<0.025). The addition of 25 microg/kg of nicotine significantly (p<0.025) reversed the dizocilpine-induced reduction of correct rejection. This study shows that dizocilpine reduces signal detection accuracy in a dose-dependent fashion. Nicotine can partially counteract an aspect of this reduction by reversing the dizocilpine-induced reduction of correct rejection.

Authors
Rezvani, AH; Levin, ED
MLA Citation
Rezvani, AH, and Levin, ED. "Nicotinic-glutamatergic interactions and attentional performance on an operant visual signal detection task in female rats." Eur J Pharmacol 465.1-2 (March 28, 2003): 83-90.
PMID
12650836
Source
pubmed
Published In
European Journal of Pharmacology
Volume
465
Issue
1-2
Publish Date
2003
Start Page
83
End Page
90

Reliabilities and intercorrelations of reported and objective measures of smoking in patients with schizophrenia.

We examined the test-retest reliabilities of reported and objective measures of smoking, and the intercorrelations among these measures, in acutely psychotic patients with schizophrenia to determine whether severe psychiatric illness affects the utility of these variables. All measures demonstrated good test-retest reliability. Objective measures of smoking were consistently intercorrelated and should be the preferred outcome measures in studies testing strategies to reduce smoking.

Authors
Yang, YK; McEvoy, JP; Wilson, WH; Levin, ED; Rose, JE
MLA Citation
Yang, YK, McEvoy, JP, Wilson, WH, Levin, ED, and Rose, JE. "Reliabilities and intercorrelations of reported and objective measures of smoking in patients with schizophrenia." Schizophr Res 60.1 (March 1, 2003): 9-12.
PMID
12505133
Source
pubmed
Published In
Schizophrenia Research
Volume
60
Issue
1
Publish Date
2003
Start Page
9
End Page
12

A zebrafish model for studying the neurobehavioral impacts of developmental chlorpyrifos exposure.

Authors
Swain, H; Donerly, S; Chrysanthis, E; Yacsin, K; Linney, E; Levin, ED
MLA Citation
Swain, H, Donerly, S, Chrysanthis, E, Yacsin, K, Linney, E, and Levin, ED. "A zebrafish model for studying the neurobehavioral impacts of developmental chlorpyrifos exposure." March 2003.
Source
wos-lite
Published In
Toxicological Sciences (Elsevier)
Volume
72
Publish Date
2003
Start Page
129
End Page
129

Learning impairment caused by infusion of a toxin produced by Pfiesteria piscicida into the hippocampus of rats.

Authors
Levin, ED; Blackwelder, WR; Glasgow, HB; Burkholder, JM; Moeller, PR; Ramsdell, JS
MLA Citation
Levin, ED, Blackwelder, WR, Glasgow, HB, Burkholder, JM, Moeller, PR, and Ramsdell, JS. "Learning impairment caused by infusion of a toxin produced by Pfiesteria piscicida into the hippocampus of rats." March 2003.
Source
wos-lite
Published In
Toxicological Sciences (Elsevier)
Volume
72
Publish Date
2003
Start Page
71
End Page
71

Nicotinic mechanisms of memory: effects of acute local DHbetaE and MLA infusions in the basolateral amygdala.

Nicotine has been shown to improve working memory. The neural mechanisms underlying this effect are still being determined. The ventral hippocampus is critical for nicotinic effects on memory. Local ventral hippocampal infusions of either the nicotinic alpha7 nicotinic receptor antagonist methyllycaconitine (MLA) or the alpha4beta2 nicotinic receptor antagonist dihydro-beta-erythroidine (DHbetaE) caused working memory impairments, but no additive effects were seen. Other areas, such as the amygdala, also likely play important roles in nicotinic effects on memory. Amygdalar lesions cause memory impairment and there is a dense concentration of nicotinic receptors in the basolateral amygdala. The current study used local basolateral amygdalar infusions of the nicotinic antagonists MLA and DHbetaE to determine the involvement of alpha7 and alpha4beta2 nicotinic receptors in spatial working and reference memory. Rats (n=8) were trained in the 16-arm radial maze and were implanted with bilateral infusion cannulae into the basolateral amygdala. Acute infusions of MLA (6.75 micro g/side, P<0.0005) or DHbetaE (3.38 micro g/side, P<0.025) caused significant working memory impairments. When given together MLA and DHbetaE did not produce an additive effect. In fact, the 6.75 micro g/kg dose of DHbetaE produced a significant (P<0.0005) attenuation of the MLA-induced working memory impairment. Significant effects were not seen with reference memory or response latency. Nicotinic systems in the basolateral amygdala, as in the ventral hippocampus, are important for spatial working memory. In both the basolateral amygdala and the ventral hippocampus, MLA and DHbetaE individually caused working memory impairments. The lowest effective dose of DHbetaE was lower in the basolateral amygdala than in the ventral hippocampus. In both the basolateral amygdala and the ventral hippocampus, combined MLA and DHbetaE treatment did not produce additive working memory deficits. Unlike in the ventral hippocampus, the addition of DHbetaE to MLA in the basolateral amygdala significantly reduced the MLA-induced working memory deficit.

Authors
Addy, NA; Nakijama, A; Levin, ED
MLA Citation
Addy, NA, Nakijama, A, and Levin, ED. "Nicotinic mechanisms of memory: effects of acute local DHbetaE and MLA infusions in the basolateral amygdala." Brain Res Cogn Brain Res 16.1 (March 2003): 51-57.
PMID
12589888
Source
pubmed
Published In
Cognitive Brain Research
Volume
16
Issue
1
Publish Date
2003
Start Page
51
End Page
57

Chlorpyrifos exposure of developing zebrafish: effects on survival and long-term effects on response latency and spatial discrimination.

Chlorpyrifos (CPF) is a widely used insecticide, which has been shown to interfere with neurobehavioral development. Rat models have been key in demonstrating that prenatal CPF exposure causes choice accuracy deficits and motor alterations, which persist into adulthood. Complementary nonmammalian models can be useful in determining the molecular mechanisms underlying the persisting behavioral effects of developmental CPF exposure. Zebrafish with their clear chorion and extensive developmental information base provide an excellent model for assessment of molecular processes of toxicant impacted neurodevelopment. To facilitate the use of the zebrafish model and to compare it to the more typical rodent models, the behavioral phenotype of CPF toxicity in zebrafish must be well characterized. Our laboratory has developed methods for assessing spatial discrimination learning in zebrafish, which can differentiate response latency from choice accuracy in a three chambered fish tank. Low and high doses of CPF (10 and 100 ng/ml on days 1-5 postfertilization) both had significant persisting effects on both spatial discrimination and response latency over 18 weeks of testing. The high, but not the low dose, significantly accelerated mortality rates of the fish during the study from 20-38 weeks of age. Developmental exposure to either 10 or 100 ng/ml of CPF caused significant spatial discrimination impairments in zebrafish when they were adults. The impairment caused by 10 ng/ml was seen during early but not later testing, while the impairment caused by 100 ng/ml became more pronounced with continued testing. The higher dose caused a more pervasive impairment. The 10 and 100 ng/ml doses had opposite effects on response latency. The low 10 ng/ml dose significantly slowed response latency, while the high 100 ng/ml dose significant increased response latency. Both of these effects diminished with continued testing. CPF exposure during early development caused clear behavioral impairments, which lasted throughout adulthood in zebrafish. The molecular mechanisms by which early developmental CPF exposure produces these behavioral impairments expressed in adulthood can now be studied in the zebrafish model.

Authors
Levin, ED; Chrysanthis, E; Yacisin, K; Linney, E
MLA Citation
Levin, ED, Chrysanthis, E, Yacisin, K, and Linney, E. "Chlorpyrifos exposure of developing zebrafish: effects on survival and long-term effects on response latency and spatial discrimination." Neurotoxicol Teratol 25.1 (January 2003): 51-57.
PMID
12633736
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
25
Issue
1
Publish Date
2003
Start Page
51
End Page
57

Erratum: Chlorpyrifos exposure of developing zebrafish: Effects on survival and long-term effects on response latency and spatial discrimination (Neurotoxicology and Teratology (2003) 25 (51-57))

Authors
Levin, ED; Chrysanthis, E; Yacisin, K; Linney, E
MLA Citation
Levin, ED, Chrysanthis, E, Yacisin, K, and Linney, E. "Erratum: Chlorpyrifos exposure of developing zebrafish: Effects on survival and long-term effects on response latency and spatial discrimination (Neurotoxicology and Teratology (2003) 25 (51-57))." Neurotoxicology and Teratology 25.5 (2003): 639--.
Source
scival
Published In
Neurotoxicology and Teratology
Volume
25
Issue
5
Publish Date
2003
Start Page
639-
DOI
10.1016/S0892-0362(03)00077-1

Behavioral Toxicology Society 2002 annual meeting report

Authors
Levin, ED
MLA Citation
Levin, ED. "Behavioral Toxicology Society 2002 annual meeting report." Neurotoxicology and Teratology 25.1 (2003): 77-80.
Source
scival
Published In
Neurotoxicology and Teratology
Volume
25
Issue
1
Publish Date
2003
Start Page
77
End Page
80
DOI
10.1016/S0892-0362(02)00355-0

Effects of nicotine and mecamylamine on choice accuracy in an operant visual signal detection task in female rats.

RATIONALE: During the past decade, central nicotinic systems have been shown in both experimental animals and humans to play an important role in cognitive function. However, the way in which specific aspects of cognitive function are affected by nicotinic systems has remained unclear. In humans, the most pronounced action of nicotine is to improve attention, but in rats, memory improvement is more easily seen. This may be due to differences in methods for assessing attention in rats and humans or to species differences in the roles of nicotinic systems in cognitive function. In the current study, we explored the effects of nicotine and mecamylamine using an operant visual signal detection task designed to model sustained attention processes common to rats and humans. METHODS: Adult female rats ( n=35) were trained to perform the signal detection task to a stable baseline of about 75% accuracy. The rats were then assigned to two subgroups of high and low accuracy based on overall accuracy (hits and correct rejections) at the end of training. All rats were then injected (SC, 10 min before testing) with saline or different doses of nicotine (0.0125, 0.025, 0.05, 0.1, 0.2 and 0.4 mg/kg) or the nicotinic antagonist mecamylamine (1, 2 and 4 mg/kg). RESULTS: A low dose range of nicotine (0.0125, 0.025, and 0.05 mg/kg) caused a dose-related increase in percent correct rejection. This dose range did not affect correct detections of the signal (percent hit). Higher doses of nicotine (0.1, 0.2 and 0.4 mg/kg) did not affect percent correct rejection, but did have a time-dependent effect on percent hit. Early in the session, the higher doses of nicotine reduced percent hit, whereas during the later part of the session higher doses of nicotine increased percent hit. Effects of nicotine did not differ between the high- and low-accuracy rats. Mecamylamine decreased choice accuracy, reducing both percent hit and percent correct rejection. Mecamylamine reduced percent hit in the low-accuracy rats at a lower drug dose than in the high-accuracy rats. CONCLUSIONS: These results support the involvement of nicotinic systems in attention in rats, as has been shown in humans. This rat model of sustained attention may provide a good approach to studying neural mechanisms underlying the effects of nicotinic cholinergic receptors on attention and a means to evaluate the potential of novel nicotinic agonists to counteract attentional dysfunction.

Authors
Rezvani, AH; Bushnell, PJ; Levin, ED
MLA Citation
Rezvani, AH, Bushnell, PJ, and Levin, ED. "Effects of nicotine and mecamylamine on choice accuracy in an operant visual signal detection task in female rats." Psychopharmacology (Berl) 164.4 (December 2002): 369-375.
PMID
12457266
Source
pubmed
Published In
Psychopharmacology
Volume
164
Issue
4
Publish Date
2002
Start Page
369
End Page
375
DOI
10.1007/s00213-002-1221-0

Nicotinic receptor subtypes and cognitive function.

Nicotinic receptor systems are involved in a wide variety of behavioral functions including cognitive function. Nicotinic medications may provide beneficial treatment for cognitive dysfunction such as Alzheimer's disease, schizophrenia, and attention deficit hyperactivity disorder (ADHD). Nicotine has been shown to improve attentional performance in all of these disorders. Better efficacy with fewer side effects might be achieved with novel nicotinic ligands selective for particular nicotinic subtypes. To develop these novel selective nicotinic ligands it is important to use animal models to determine the critical neurobehavioral bases for nicotinic involvement in cognitive function. Nicotine-induced cognitive improvement in rats is most consistently seen in working memory tasks. We have found that both acute and chronic nicotine administration significantly improves working memory performance of rats in the radial-arm maze. The pharmacologic and anatomic mechanisms for this effect have been examined in our laboratory in a series of local drug infusion studies. Both alpha 4 beta 2 and alpha 7 nicotinic receptors in the ventral hippocampus and basolateral amygdala are involved in working memory function. Working memory impairments were caused by local infusion of either alpha 4 beta 2 or alpha 7 antagonists. Ventral hippocampal alpha 4 beta 2 blockade-induced working memory deficits are reversed by chronic systemic nicotine treatment, while ventral hippocampal alpha 7 blockade-induced working memory deficits were not found to be reversed by the same nicotine regimen. Interestingly, alpha 4 beta 2 and alpha 7 induced deficits were not found to be additive in either the ventral hippocampus or the basolateral amygdala. In fact, in the amygdala, alpha 7 antagonist cotreatment actually reversed the working memory impairment caused by alpha 4 beta 2 antagonist administration. These studies of the neural nicotinic mechanisms underlying cognitive function are key for opening avenues for development of safe and effective nicotinic treatments for cognitive dysfunction.

Authors
Levin, ED
MLA Citation
Levin, ED. "Nicotinic receptor subtypes and cognitive function." J Neurobiol 53.4 (December 2002): 633-640. (Review)
PMID
12436426
Source
pubmed
Published In
Journal of Neurobiology
Volume
53
Issue
4
Publish Date
2002
Start Page
633
End Page
640
DOI
10.1002/neu.10151

Prenatal chlorpyrifos exposure in rats causes persistent behavioral alterations.

Use of chlorpyrifos (CPF) has been curtailed due to its developmental neurotoxicity. In rats, postnatal CPF administration produces lasting changes in cognitive performance, but less information is available about the effects of prenatal exposure. We administered CPF to pregnant rats on gestational days (GD) 17-20, a peak period of neurogenesis, using doses (1 or 5 mg/kg/day) below the threshold for fetal growth impairment. We then evaluated performance in the T-maze, Figure-8 apparatus and 16-arm radial maze, beginning in adolescence and continuing into adulthood. CPF elicited initial locomotor hyperactivity in the T-maze. Females showed slower habituation in the Fig. 8 maze; no effects were seen in males. In the radial-arm maze, females showed impaired choice accuracy for both working and reference memory and again, males were unaffected. Despite the deficits, all animals eventually learned the maze with continued training. At that point, we challenged them with the muscarinic antagonist, scopolamine, to determine the dependence of behavioral performance on cholinergic function. Whereas control females showed impairment with scopolamine, CPF-exposed females did not, implying that the delayed acquisition of the task had been accomplished through alternative mechanisms. The differences were specific to muscarinic circuits, as control and CPF groups responded similarly to the nicotinic antagonist, mecamylamine. Surprisingly, adverse effects of CPF were greater in the group receiving 1 mg/kg as compared to 5 mg/kg. Promotional effects of acetylcholine (ACh) on cell differentiation may thus help to offset CPF-induced developmental damage that occurs through other noncholinergic mechanisms. Our results indicate that late prenatal exposure to CPF induces long-term changes in cognitive performance that are distinctly gender-selective. Additional defects may be revealed by similar strategies that subject the animals to acute challenges, thus, uncovering the adaptive mechanisms that maintain basal performance.

Authors
Levin, ED; Addy, N; Baruah, A; Elias, A; Christopher, NC; Seidler, FJ; Slotkin, TA
MLA Citation
Levin, ED, Addy, N, Baruah, A, Elias, A, Christopher, NC, Seidler, FJ, and Slotkin, TA. "Prenatal chlorpyrifos exposure in rats causes persistent behavioral alterations." Neurotoxicol Teratol 24.6 (November 2002): 733-741.
PMID
12460655
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
24
Issue
6
Publish Date
2002
Start Page
733
End Page
741

Nicotine interactions with haloperidol, clozapine and risperidone and working memory function in rats.

Nicotine has been shown in a variety of studies to improve memory performance. The cognitive effects of nicotine are particularly important with regard to schizophrenia. In the current studies nicotine interactions with three different antipsychotic drugs, haloperidol, clozapine and risperidone, were assessed with regard to memory function. Female Sprague-Dawley rats were trained on the radial-arm maze to asymptotic levels of choice accuracy. They were then administered nicotine alone or in combination with haloperidol, clozapine or risperidone. Acute haloperidol (0.04 mg/kg) did not by itself affect memory performance. Co-administration of haloperidol with nicotine, however, decreased memory performance compared with nicotine administration in isolation. Acute clozapine (1.25 and 2.5 mg/kg) caused a significant memory impairment, an effect reversed by acute nicotine co-treatment. Risperidone (0.05 mg/kg), like haloperidol, did not by itself affect memory performance. Risperidone co-administration with nicotine, however, did significantly attenuate the improvement caused by nicotine administration in isolation. The similar interaction of haloperidol and risperidone with nicotine may be due to their common action of blocking D(2) receptors, a mechanism of action not shared by clozapine. In contrast to the interaction of nicotine with haloperidol or risperidone, nicotine effectively reversed clozapine-induced memory impairment. These studies demonstrate interactions between nicotine and antipsychotic drugs in terms of memory, which may have important impacts on the treatment of schizophrenia.

Authors
Addy, N; Levin, ED
MLA Citation
Addy, N, and Levin, ED. "Nicotine interactions with haloperidol, clozapine and risperidone and working memory function in rats." Neuropsychopharmacology 27.4 (October 2002): 534-541.
PMID
12377390
Source
pubmed
Published In
Neuropsychopharmacology (Nature)
Volume
27
Issue
4
Publish Date
2002
Start Page
534
End Page
541
DOI
10.1016/S0893-133X(02)00327-5

Nicotinic treatment for cognitive dysfunction.

Nicotinic medications may provide beneficial therapeutic treatment for cognitive dysfunction such as Alzheimer's disease, schizophrenia and attention deficit hyperactivity disorder (ADHD). For development of nicotinic treatments we are fortunate to have a well characterized lead compound, nicotine. Transdermal nicotine patches offer a way to deliver measured doses of nicotine in a considerably safer fashion than the more traditional means of administration, tobacco smoking. We have found that transdermal nicotine significantly improves attentional function in people with Alzheimer's disease, schizophrenia or ADHD as well as normal nonsmoking adults. To follow-up on this proof of principal that nicotinic treatment of cognitive dysfunction holds promise, it is important to use animal models to determine the critical neurobehavioral bases for nicotinic involvement in cognitive function so that more selective nicotinic analogues that improve cognitive function with fewer side effects can be developed. We have found with local infusion in rat studies that the hippocampus and amygdala are important substrates for nicotinic effects on working memory function. Both alpha7 and alpha4beta2 nicotinic receptors are involved in working memory. Nicotinic interactions with dopaminergic and glutaminergic systems are also important in the basis of cognitive function. Studies of the neural nicotinic mechanisms underlying cognitive function are key for opening avenues for development of safe and effective nicotinic treatments for cognitive dysfunction.

Authors
Levin, ED; Rezvani, AH
MLA Citation
Levin, ED, and Rezvani, AH. "Nicotinic treatment for cognitive dysfunction." Curr Drug Targets CNS Neurol Disord 1.4 (August 2002): 423-431. (Review)
PMID
12769614
Source
pubmed
Published In
Current drug targets. CNS and neurological disorders
Volume
1
Issue
4
Publish Date
2002
Start Page
423
End Page
431

Nicotine-alcohol interactions and cognitive function in rats.

Nicotine and ethanol are the most widely abused drugs in the world. They are very often used and abused together. However, little is known about the functional interaction of nicotine and ethanol. The current project studied the interactive effects of nicotine and ethanol on working memory in the eight-arm radial maze. Adult female rats were trained on a radial arm maze for 18 sessions to reach asymptotic levels of choice accuracy. During the maintenance phase of radial arm maze testing, which indexed working memory function, the rats were injected with nicotine (0, 0.15, 0.3, 0.6, and 1.2 mg/kg sc, 20 min before testing) with and without ethanol pretreatment (0 or 1.5 g/kg, 16% v/v ip, 30 min before testing). All animals received the treatments in a counterbalanced order with at least 1 week between treatments. Higher doses of nicotine had a significant interaction with ethanol in terms of radial arm maze choice accuracy. Nicotine plus ethanol coadministration precipitated a significant choice accuracy impairment at doses that when given alone had no effect on performance. At the lower dose range of nicotine, ethanol coadministration eliminated the nicotine-induced memory improvement. No significant effects were seen with either nicotine or ethanol treatment or their interaction on response latency in the radial arm maze. The nicotine-ethanol interactive effects on memory were compared with the interaction of their well-characterized hypothermic effects. Nicotine and alcohol, when injected separately or in combination, induced hypothermia with no significant interactive effect. This study found that ethanol blocked low-dose nicotine-induced memory improvement and precipitated memory impairment with high-dose nicotine treatment. This interaction may be an important consideration for nicotine and ethanol coabuse and the possible therapeutic use of nicotinic drugs for memory dysfunction.

Authors
Rezvani, AH; Levin, ED
MLA Citation
Rezvani, AH, and Levin, ED. "Nicotine-alcohol interactions and cognitive function in rats." Pharmacol Biochem Behav 72.4 (July 2002): 865-872.
PMID
12062576
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
72
Issue
4
Publish Date
2002
Start Page
865
End Page
872

Developmental neurotoxicity of chlorpyrifos: Defining the vulnerable period

Authors
Qiao, D; Seidler, FJ; Levin, ED; Padilla, S; Slotkin, TA
MLA Citation
Qiao, D, Seidler, FJ, Levin, ED, Padilla, S, and Slotkin, TA. "Developmental neurotoxicity of chlorpyrifos: Defining the vulnerable period." FASEB JOURNAL 16.5 (March 22, 2002): A949-A949.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
16
Issue
5
Publish Date
2002
Start Page
A949
End Page
A949

Chronic inhibition of alpha4beta2 nicotinic receptors in the ventral hippocampus of rats: impacts on memory and nicotine response.

RATIONALE: Acute and chronic systemic nicotine administration has been shown to cause significant spatial memory improvement. The critical nicotinic receptor subtypes for this effect and their location are still being determined. Nicotinic receptors in the ventral hippocampus have been found to be critically involved in memory. Acute ventral hippocampal infusions of dihydro-beta-erythroidine (DHbetaE), an alpha4beta2 nicotinic receptor antagonist, impaired spatial memory of rats in the radial-arm maze. OBJECTIVES: The current study used chronic ventral hippocampal infusion of DHbetaE as a model of nicotinic receptor loss such as that which occurs in Alzheimer's disease. The therapeutic effect of systemic nicotine treatment in reversing the DHbetaE-induced memory impairment was determined. METHODS: Rats were pretrained to asymptotic levels of performance on the eight-arm radial maze. Then, they were implanted with bilateral infusion cannulae in the ventral hippocampus, through which 0, 33.3, or 100 microg/side/day of DHbetaE was continuously infused for 4 weeks. The rats were retested on the eight-arm maze throughout infusion period and after withdrawal, and the interaction of acute systemic nicotine injections on memory was tested. RESULTS: The higher (100 microg/side/day) but not the lower (33.3 microg/side/day) DHbetaE dose caused a significant spatial memory impairment. Acute systemic nicotine injections (0, 0.1, 0.2, and 0.4 mg/kg, subcutaneous) attenuated the memory impairing effects of 100 microg/side/day of DHbetaE. There was no significant effect on response latency with the chronic DHbetaE infusion. Acute systemic nicotine infusions did significantly speed responding, an effect which was reversed by chronic hippocampal infusions of DHbetaE. After withdrawal there were no significant lasting effects on choice accuracy or response latency. Wet-dog shakes were significantly elevated during chronic hippocampal DHbetaE administration with no effect during the withdrawal period. CONCLUSIONS: These results indicate that chronic inhibition of a subset of nicotinic receptors in the hippocampus results in a significant impairment in the spatial memory choice accuracy. The ability of nicotine to attenuate the impairment supports the development of nicotinic agonist therapy of syndromes, such as Alzheimer's disease, that involve a chronic decrease in the activity of the alpha4beta2 nicotinic receptors and memory impairment.

Authors
Arthur, D; Levin, ED
MLA Citation
Arthur, D, and Levin, ED. "Chronic inhibition of alpha4beta2 nicotinic receptors in the ventral hippocampus of rats: impacts on memory and nicotine response." Psychopharmacology (Berl) 160.2 (March 2002): 140-145.
PMID
11875631
Source
pubmed
Published In
Psychopharmacology
Volume
160
Issue
2
Publish Date
2002
Start Page
140
End Page
145
DOI
10.1007/s00213-001-0961-6

Extracellular superoxide dismutase overexpression protects against aging-induced cognitive impairment in mice.

Extracellular superoxide dismutase (EC-SOD) controls the availability of extracellular superoxide and appears to play a role in controlling oxidative stress and intercellular signaling. Whether EC-SOD overexpression would help or hinder neurobehavioral function appears to depend on the age of the individual. In young adult mice, we have found that EC-SOD overexpression can interfere with learning on the radial-arm maze, possibly by reducing control over nitric oxide neurotransmission. In aged mice, we found, in the current study, that EC-SOD overexpression greatly improves learning on the radial-arm maze. Control (N = 17) and EC-SOD overexpressing mice (N = 13) acquired the 8-arm radial maze over 21 sessions of training. The EC-SOD overexpressing mice had significantly better choice accuracy than the control mice (p < 0.005). The EC-SOD overexpressing mice averaged 6.34+/-0.22 correct arm entries before an error (entries to repeat) during the acquisition phase, while the control mice averaged 5.18+/-0.22 entries to repeat. EC-SOD genotype did not cause a main effect on response latency. The advantage held by the EC-SOD overexpressing mice persisted during the eight-session post-acquisition phase of testing (p < 0.01). When there was a shift from high to low levels of motivation by reducing the period of food restriction before testing, the EC-SOD overexpression-induced improvement was reduced slightly, but it was still significant compared with the wild-type controls (p < 0.025). Then, after 4 months of no testing, the mice were tested for retention and reacquisition of performance on the radial-arm maze. The EC-SOD overexpressing mice maintained their significantly better choice accuracy (p < 0.05). Enhancement of EC-SOD activity appears to improve learning and memory performance, specifically in aging mice. EC-SOD mimetic treatment during the course of aging may hold promise for aging-induced cognitive impairment.

Authors
Levin, ED; Christopher, NC; Lateef, S; Elamir, BM; Patel, M; Liang, L-P; Crapo, JD
MLA Citation
Levin, ED, Christopher, NC, Lateef, S, Elamir, BM, Patel, M, Liang, L-P, and Crapo, JD. "Extracellular superoxide dismutase overexpression protects against aging-induced cognitive impairment in mice." Behav Genet 32.2 (March 2002): 119-125.
PMID
12036109
Source
pubmed
Published In
Behavior Genetics
Volume
32
Issue
2
Publish Date
2002
Start Page
119
End Page
125

A naturalistic study of the effects of smoking on the cognitive side effects of ECT.

Authors
Rossler, IB; Johnson, RC; Krystal, AD; Weiner, RD; Levin, ED; Logue, P; Coffey, CE; Edwards, CL
MLA Citation
Rossler, IB, Johnson, RC, Krystal, AD, Weiner, RD, Levin, ED, Logue, P, Coffey, CE, and Edwards, CL. "A naturalistic study of the effects of smoking on the cognitive side effects of ECT." JOURNAL OF ECT 18.1 (March 2002): 64-64.
Source
wos-lite
Published In
Journal of ECT
Volume
18
Issue
1
Publish Date
2002
Start Page
64
End Page
64

Persistence of nicotinic agonist RJR 2403-induced working memory improvement in rats

Authors
Levin, ED; Christopher, NC
MLA Citation
Levin, ED, and Christopher, NC. "Persistence of nicotinic agonist RJR 2403-induced working memory improvement in rats." Drug Development Research 55.2 (February 2002): 97-103.
Source
crossref
Published In
Drug Development Research
Volume
55
Issue
2
Publish Date
2002
Start Page
97
End Page
103
DOI
10.1002/ddr.10024

Hippocampal alpha 7 and alpha 4 beta 2 nicotinic receptors and working memory.

Nicotine and other nicotinic receptor agonists have been found in a variety of studies to improve memory, while nicotinic receptor blockade can impair memory. The critical neural mechanisms for nicotinic involvement with memory are still under investigation. Initial evidence supports the involvement of the ventral hippocampus. Lesions in this area block nicotine-induced memory improvement and mecamylamine-induced impairment. Local ventral hippocampal application of the nicotinic channel blocker mecamylamine impairs memory in the 8-arm radial maze. Both alpha 4 beta 2 and alpha 7 nicotinic receptors seem to be involved. Ventral hippocampal infusions of high doses of the alpha 4 beta 2 nicotinic antagonist dihydro-beta-erythrodine (DH beta E) and the alpha 7 nicotinic antagonist methyllycaconitine (MLA) impair memory performance on the 8-arm radial maze. However, high doses of these drugs may limit specificity and they cause preconvulsant effects, which in themselves may affect memory. The current study used the more challenging 16-arm radial maze to determine the effects of lower doses of these drugs on memory and to differentiate effects on working and reference memory. Adult female Sprague-Dawley rats were trained on a working and reference memory task in the 16-arm radial maze and then were implanted with bilateral chronic guide cannulae directed to the ventral hippocampus. After recovery from surgery, the rats received acute intrahippocampal infusions of dose combinations of DH beta E and MLA. In the first study, DH beta E (0 and 6.75 microg/side) and MLA (0, 6.75, 13.5 and 27 microg/side) were administered in a counter-balanced order. In the second study, lower doses of DH beta E (0, 1.6375, 3.275 and 6.75 microg/side) were administered alone or with MLA (0 and 6.75 microg/side) in a counter-balanced order. In the first study, DH beta E caused a significant increase in both working and reference memory errors. MLA at a dose of 27 microg/side caused a significant increase in working memory errors, but this dose had no significant effect on reference memory errors. Interestingly, no additive effects were seen with combined administration of DH beta E and MLA in this study, and at the doses used, no effects were seen on response latency. In the second study, lower doses of DH beta E did not cause a significant deficit in working memory performance. Co-administration of MLA with these subthreshold doses did precipitate a memory impairment. The current results confirm the specificity of the memory deficits caused by these drugs. These results support the involvement of alpha 4 beta 2 and alpha 7 nicotinic receptors in the ventral hippocampus as being critical for memory function.

Authors
Levin, ED; Bradley, A; Addy, N; Sigurani, N
MLA Citation
Levin, ED, Bradley, A, Addy, N, and Sigurani, N. "Hippocampal alpha 7 and alpha 4 beta 2 nicotinic receptors and working memory." Neuroscience 109.4 (2002): 757-765.
PMID
11927157
Source
pubmed
Published In
Neuroscience
Volume
109
Issue
4
Publish Date
2002
Start Page
757
End Page
765

Effect of long-term stabilization of cationic liposomes as defibrotide delivery system for antithrombotic activity

The general goal of this study was to produce cationic liposome formulations suitable for the in vivo administration of defibrotide (DFT) (a DNA-based drug) and to investigate in vitro and in vivo the stability of such a formulation. This article describes the freeze-drying of cationic liposomes using as cryoprotectants different carbohydrates, such as sorbitol, mannitol, and sucrose. Liposome characteristics before and after freeze-drying, such as size, morphology, and ability in complexing a DNA-based drug, have been investigated. The in vitro studies indicate that cationic liposomes sufficiently maintain the initial characteristics after lyophilization and rehydration including the ability to complex DFT. The in vivo data show that lyophilized cationic liposome formulations can be safely stored for at least 3 months. Before in vivo use, liposomes can be rehydrated with DFT solutions, resulting in the formation of stable complexes retaining an in vivo activity comparable to that of the freshly prepared formulation. © 2002 Wiley-Liss, Inc.

Authors
Levin, ED; Christopher, NC
MLA Citation
Levin, ED, and Christopher, NC. "Effect of long-term stabilization of cationic liposomes as defibrotide delivery system for antithrombotic activity." Drug Development Research 55.2 (2002): 127-138.
Source
scival
Published In
Drug Development Research
Volume
55
Issue
2
Publish Date
2002
Start Page
127
End Page
138
DOI
10.1002/ddr.10041

Ventral hippocampal alpha 7 nicotinic receptor blockade and chronic nicotine effects on memory performance in the radial-arm maze.

Chronic nicotine administration has been shown to significantly improve working memory. Nicotinic involvement in memory function critically involves the ventral hippocampus. Local ventral hippocampal infusions of the nicotinic antagonists mecamylamine, dihydro-beta-erythroidine (DH beta E) and methyllycaconitine (MLA) significantly impair working memory. The impairment caused by hippocampal infusion of the alpha 4 beta 2 antagonist DH beta E is reversed by chronic systemic nicotine. This study determined the interaction of chronic systemic nicotine with acute ventral hippocampal infusions of the alpha 7 antagonist MLA. Adult female Sprague-Dawley rats were trained on an 8-arm radial maze working memory task. Then they underwent ventral hippocampal cannulation and received sc implants of minipumps delivering nicotine (0 or 5 mg/kg/day for 28 days). Acute ventral hippocampal infusions of MLA (0, 4.88, 14.64 and 43.92 microg/side) were given during 3-4 weeks of chronic nicotine. MLA caused a significant dose-related memory impairment. In the rats not receiving nicotine, the 14.64 and 43.92 microg/side MLA doses caused significant memory impairment. Chronic systemic nicotine exposure did not block the MLA-induced memory impairment. Comparing the current results with MLA with previous results with DH beta E, equimolar ventral hippocampal DH beta E more effectively impaired memory than MLA, but the DH beta E-induced impairment was more effectively reversed by chronic systemic nicotine administration.

Authors
Bettany, JH; Levin, ED
MLA Citation
Bettany, JH, and Levin, ED. "Ventral hippocampal alpha 7 nicotinic receptor blockade and chronic nicotine effects on memory performance in the radial-arm maze." Pharmacol Biochem Behav 70.4 (December 2001): 467-474.
PMID
11796146
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
70
Issue
4
Publish Date
2001
Start Page
467
End Page
474

Specificity of cognitive impairment from Pfiesteria piscicida exposure in rats: attention and visual function versus behavioral plasticity.

Pfiesteria piscicida is a toxic dinoflagellate that has caused massive fish kills in estuaries along the East Coast of the United States, and exposure of humans to toxic Pfiesteria has been associated with cognitive impairment. A visual signal detection task was used to determine the possible importance of attentional and visual processes in Pfiesteria effects on cognitive function. Adult female rats were trained to perform the signal detection task. After training, the rats were injected subcutaneously with fish culture water containing toxic Pfiesteria (35,600 or 106,800 cells of Pfiesteria/kg of rat body weight) or with (control) fish culture water containing no Pfiesteria. Effects of toxic Pfiesteria on maintenance of signal detection behavior were assessed for 2 weeks after treatment. Then, the signal-response contingencies were reversed. After the discrimination was reestablished on the reversed levers, the rats received a second dose of toxic Pfiesteria. The rats were again tested for 2 weeks, after which a second reversal was imposed. Pfiesteria did not affect behavior in the signal detection task during 2 weeks of prereversal testing after either exposure. However, a significant Pfiesteria-induced deficit emerged when the signal-response contingencies were reversed. These findings suggest that Pfiesteria-induced deficits emerge during periods of behavioral transition and not during performance of previously learned tasks.

Authors
Rezvani, AH; Bushnell, PJ; Burkholder, JM; Glasgow, HB; Levin, ED
MLA Citation
Rezvani, AH, Bushnell, PJ, Burkholder, JM, Glasgow, HB, and Levin, ED. "Specificity of cognitive impairment from Pfiesteria piscicida exposure in rats: attention and visual function versus behavioral plasticity." Neurotoxicol Teratol 23.6 (November 2001): 609-616.
PMID
11792529
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
23
Issue
6
Publish Date
2001
Start Page
609
End Page
616

A rat model of the cognitive impairment from Pfiesteria piscicida exposure.

Pfiesteria piscicida Steidinger & Burkholder, an estuarine dinoflagellate known to kill fish, has also been associated with neurocognitive deficits in humans. We have developed a rat model to determine the cause-and-effect relationship between exposure to Pfiesteria-containing water and cognitive impairment and to determine the neurobehavioral mechanisms underlying the Pfiesteria effect. The rat model of Pfiesteria toxicity can also provide important information concerning the toxin or toxins responsible for neurocognitive deficits resulting from Pfiesteria exposure. With the rat model we have repeatedly documented a Pfiesteria-induced choice accuracy impairment during radial-arm maze learning. The Pfiesteria-induced impairment was relatively specific to the acquisition phase of training. When rats were pretrained, Pfiesteria treatment did not affect performance. However, when these same rats were retrained on another task, the Pfiesteria-induced impairment became evident. Pfiesteria-induced effects were also seen in a locomotor activity test in the figure-8 apparatus and selected components of the functional observational battery. Pfiesteria effects on choice accuracy in the radial-arm maze in rats constitute a critical component of the model of Pfiesteria toxicity, as the hallmark of Pfiesteria toxicity in humans is cognitive dysfunction. Our finding that analysis of the first six sessions of radial-arm maze testing is sufficient for determining the effect means that this test will be useful as a rapid screen for identifying the critical neurotoxin(s) of Pfiesteria in future studies.

Authors
Levin, ED
MLA Citation
Levin, ED. "A rat model of the cognitive impairment from Pfiesteria piscicida exposure." Environ Health Perspect 109 Suppl 5 (October 2001): 757-763.
PMID
11677185
Source
pubmed
Published In
Environmental health perspectives
Volume
109 Suppl 5
Publish Date
2001
Start Page
757
End Page
763

Persistent behavioral consequences of neonatal chlorpyrifos exposure in rats.

Chlorpyrifos (CPF) is a widely used insecticides which has been shown to alter brain cell development. The current project was conducted to determine whether there are persistent behavioral effects of early [1 mg/kg/day postnatal days (PNDs) 1-4] or late (5 mg/kg/day PNDs 11-14) postnatal CPF exposure in rats. We tested spontaneous alternation in a T-maze, locomotor activity in the Figure-8 apparatus and learning in the 16-arm radial maze, throughout adolescence and into adulthood. Exposure during either neonatal period elicited significant long-term effects on cognitive behavior. In the radial-arm maze, as has been seen previously, control male performed more accurately than control females. Early postnatal CPF exposure reversed this effect. With exposure on PNDs 1-4, females in the CPF group showed a reduction in working and reference memory errors in the radial maze, reducing their error rate to that seen in control males; in contrast, CPF-exposed males exhibited an increase in errors during the initial stages of training. When animals were exposed on PNDs 11-14 and then tested in adolescence and adulthood, males showed a significant slowing of response latency in the T-maze and the rate of habituation in the Figure-8 apparatus was slowed in both sexes. When females were challenged acutely with the muscarinic antagonist, scopolamine, they did not show reference memory impairment, whereas controls did; these results suggest that adaptations occur after CPF exposure that lead to loss of muscarinic cholinergic control of reference memory. No such changes were seen with a nicotinic cholinergic antagonist (mecamylamine). These results indicate that early neonatal exposure to CPF induces long-term changes in cognitive performance that, in keeping with the neurochemical changes seen previously, are distinctly gender-selective. Additional defects may be revealed by similar strategies that subject the animals to acute challenges, thus uncovering the adaptive mechanisms that maintain basal performance.

Authors
Levin, ED; Addy, N; Nakajima, A; Christopher, NC; Seidler, FJ; Slotkin, TA
MLA Citation
Levin, ED, Addy, N, Nakajima, A, Christopher, NC, Seidler, FJ, and Slotkin, TA. "Persistent behavioral consequences of neonatal chlorpyrifos exposure in rats." Brain Res Dev Brain Res 130.1 (September 23, 2001): 83-89.
PMID
11557096
Source
pubmed
Published In
Developmental Brain Research
Volume
130
Issue
1
Publish Date
2001
Start Page
83
End Page
89

Cognitive effects of nicotine.

Nicotine and other nicotinic agonists have been found to improve performance on attention and memory tasks. Clinical studies using nicotine skin patches have demonstrated the efficacy of nicotine in treating cognitive impairments associated with Alzheimer's disease, schizophrenia, and attention-deficit/hyperactivity disorder. Experimental animal studies have demonstrated the persistence of nicotine-induced working memory improvement with chronic exposure, in addition to the efficacy of a variety of nicotinic agonists. Mechanistic studies have found that alpha7 and alpha4beta2 nicotinic receptors in the hippocampus are critical for nicotinic involvement in cognitive function. Clinical and experimental animal studies provide mutually supporting information for the development of novel nicotinic therapies for cognitive dysfunction.

Authors
Rezvani, AH; Levin, ED
MLA Citation
Rezvani, AH, and Levin, ED. "Cognitive effects of nicotine." Biol Psychiatry 49.3 (February 1, 2001): 258-267. (Review)
PMID
11230877
Source
pubmed
Published In
Biological Psychiatry
Volume
49
Issue
3
Publish Date
2001
Start Page
258
End Page
267

Effects of chronic nicotine and methylphenidate in adults with attention deficit/hyperactivity disorder.

Acute nicotine treatment has been found to reduce symptoms of attention deficit/hyperactivity disorder in adults (E. D. Levin, C. K. Conners, et al., 1996). In this study, chronic nicotine effects were compared with placebo and methylphenidate. Acute and chronic nicotine treatment significantly attenuated the rise in hit reaction time standard error over session blocks on the Conners Continuous Performance Test (C. K. Conners et al., 1996). Acute nicotine significantly reduced severity of clinical symptoms on the Clinical Global Impressions scale (National Institute of Mental Health, 1985). Nicotine caused a significant decrease in self-report of depressive mood as measured by the Profile of Mood States test (D. M. McNair, M. Lorr, & L. F. Droppleman, 1981). This small study (40 participants) provided evidence that nicotine treatment can reduce severity of attentional deficit symptoms and produce improvement on an objective computerized attention task.

Authors
Levin, ED; Conners, CK; Silva, D; Canu, W; March, J
MLA Citation
Levin, ED, Conners, CK, Silva, D, Canu, W, and March, J. "Effects of chronic nicotine and methylphenidate in adults with attention deficit/hyperactivity disorder." Exp Clin Psychopharmacol 9.1 (February 2001): 83-90.
PMID
11519638
Source
pubmed
Published In
Experimental and Clinical Psychopharmacology
Volume
9
Issue
1
Publish Date
2001
Start Page
83
End Page
90

Spatial and non-spatial discrimination learning in zebrafish (Danio rerio)

Authors
Arthur, D; Levin, ED
MLA Citation
Arthur, D, and Levin, ED. "Spatial and non-spatial discrimination learning in zebrafish (Danio rerio)." Animal Cognition 4 (2001): 125-131. (Academic Article)
Source
manual
Published In
Animal Cognition
Volume
4
Publish Date
2001
Start Page
125
End Page
131

The nicotinic antagonist mecamylamine preferentially inhibits cocaine vs. food self-administration in rats.

Nicotinic acetylcholine systems play important roles in addiction, and nicotinic receptor stimulation stimulates dopamine release while the nicotinic antagonist mecamylamine reduces it. Reid et al. [Neuropsychopharmacology 20 (1999) 297.] recently found in human cocaine addicts that mecamylamine reduced cue-elicited cocaine craving. The current study assessed the impact of mecamylamine on cocaine self-administration in rats. Female Sprague-Dawley rats (N=7) were implanted with intravenous (iv) catheters and trained to lever press for cocaine (0.32 mg/kg/infusion FR-1 with a 60-s timeout) in 45-min sessions. After 2 weeks of training, the rats were injected with saline or mecamylamine (1, 2, or 4 mg/kg sc) 10 min before the session. They received the same dose for 1 week with 1 week of uninjected testing between doses. Mecamylamine, compared to saline, significantly (P<.05) reduced the number of cocaine infusions per session with each of these doses. This effect did not appear to be due to a generalized reduction in behavioral activity. Another set of female Sprague-Dawley rats (N=8) were trained to lever press for food reinforcement. In these rats, the 1 and 2-mg/kg mecamylamine doses had no effect on food self-administration. Significant reductions in food self-administration were not seen unless the high dose of 4-mg/kg mecamylamine was used. Nicotinic antagonist treatment reduces cocaine self-administration in rats at doses that do not cause generalized effects on food-reinforced responding. Nicotinic antagonistic treatment may be a useful new approach to treat cocaine addiction.

Authors
Levin, ED; Mead, T; Rezvani, AH; Rose, JE; Gallivan, C; Gross, R
MLA Citation
Levin, ED, Mead, T, Rezvani, AH, Rose, JE, Gallivan, C, and Gross, R. "The nicotinic antagonist mecamylamine preferentially inhibits cocaine vs. food self-administration in rats." Physiol Behav 71.5 (December 2000): 565-570.
PMID
11239676
Source
pubmed
Published In
Physiology & Behavior
Volume
71
Issue
5
Publish Date
2000
Start Page
565
End Page
570

Symposium overview: mechanism of action of nicotine on neuronal acetylcholine receptors, from molecule to behavior.

Nicotine has long been known to interact with nicotinic acetylcholine (ACh) receptors since Langley used it extensively to chart sympathetic ganglia a century ago. It has also been used as an effective insecticide. However, it was not until the 1990s that the significance of nicotine was increasingly recognized from the toxicological, pharmacological, and environmental points of view. This is partly because studies of neuronal nicotinic ACh receptors are rapidly emerging from orphan status, fueled by several lines of research. Since Alzheimer's disease is known to be associated with down-regulation of cholinergic activity in the brain, a variety of nicotine derivatives are being tested and developed for treatment of the disease. Public awareness of the adverse effects of nicotine has reached the highest level recently. Since insect resistance to insecticides is one of the most serious issues in the pest-control arena, it is an urgent requirement to develop new insecticides that act on target sites not shared by the existing insecticides. The neuronal nicotinic ACh receptor is one of them, and new nicotinoids are being developed. Thus, the time is ripe to discuss the mechanism of action of nicotine from a variety of angles, including the molecular, physiological, and behavioral points of view. This Symposium covered a wide area of nicotine studies: genetic, genomic, and functional aspects of nicotinic ACh receptors were studied, as related to anthelmintics and insecticides; interactions between ethanol and nicotine out the ACh receptor were analyzed, in an attempt to explain the well-known heavy drinker-heavy smoker correlation; the mechanisms that underlie the desensitization of ACh receptors were studied as related to nicotine action; selective pharmacological profiles of nicotine, and descriptions of some derivatives were described; and chronic nicotine infusion effects on memory were examined using animal models.

Authors
Narahashi, T; Fenster, CP; Quick, MW; Lester, RA; Marszalec, W; Aistrup, GL; Sattelle, DB; Martin, BR; Levin, ED
MLA Citation
Narahashi, T, Fenster, CP, Quick, MW, Lester, RA, Marszalec, W, Aistrup, GL, Sattelle, DB, Martin, BR, and Levin, ED. "Symposium overview: mechanism of action of nicotine on neuronal acetylcholine receptors, from molecule to behavior." Toxicol Sci 57.2 (October 2000): 193-202.
PMID
11006350
Source
pubmed
Published In
Toxicological Sciences (Elsevier)
Volume
57
Issue
2
Publish Date
2000
Start Page
193
End Page
202

Ventral hippocampal alpha4beta2 nicotinic receptors and chronic nicotine effects on memory.

Chronic nicotine administration has been repeatedly shown to facilitate working memory function in rats on the radial-arm maze. The critical neural mechanisms for this effect are still being discovered. The nicotinic nature of the chronic nicotine induced memory improvement is supported by the finding that it is blocked by chronic mecamylamine co-infusion. The hippocampus also appears to be critically important. Hippocampal ibotenic acid lesions block the effect. Within the hippocampus, we have found that the alpha4beta2 nicotinic receptor subtype is involved in memory functioning. Acute ventral hippocampal infusions of the alpha4beta2 nicotinic antagonist dihydro-beta-erythroidine (DHbetaE) significantly decreased working memory performance in the radial-arm maze. The aim of the current study was to determine the importance of alpha4beta2 receptors within the ventral hippocampus for the memory enhancing effects of chronic nicotine treatment. Adult female Sprague-Dawley rats were trained on the 8-arm radial maze and were cannulated bilaterally in the ventral hippocampus. Osmotic minipumps administering chronic nicotine at a rate of 5 mg per kg per day were also implanted in the nicotine treatment rats. Control rats received saline-only minipumps. For a period of 4 weeks after surgery, each rat received bilateral hippocampal infusions of 0, 2, 6 and 18 microg per side of DHbetaE and tested for memory performance on the radial-arm maze. Radial-arm maze choice accuracy was impaired by acute hippocampal DHbetaE infusion in a dose-related fashion. This acute hippocampal DHbetaE-induced choice accuracy impairment was eliminated by chronic systemic nicotine infusion. Chronic nicotine in combination with acute vehicle hippocampal infusion was not seen to alter choice accuracy. Response latency was not found to be altered by acute hippocampal DHbetaE in the absence of chronic nicotine administration, but it did attenuate the response latency reduction induced by chronic nicotine infusion. Wet dog shakes were not found to be affected by hippocampal DHbetaE when given without chronic nicotine. Wet dog shakes were significantly increased by chronic nicotine infusion. Intra-hippocampal DHbetaE significantly potentiated this effect. The results from the current study reinforce the hypothesis that ventral hippocampal alpha4beta2 nicotinic receptors are important for memory function. These receptors may also have a role to play in the development of other aspects of behavior associated with chronic nicotine treatment.

Authors
Bancroft, A; Levin, ED
MLA Citation
Bancroft, A, and Levin, ED. "Ventral hippocampal alpha4beta2 nicotinic receptors and chronic nicotine effects on memory." Neuropharmacology 39.13 (October 2000): 2770-2778.
PMID
11044746
Source
pubmed
Published In
Neuropharmacology
Volume
39
Issue
13
Publish Date
2000
Start Page
2770
End Page
2778

Binge pattern ethanol exposure in adolescent and adult rats: differential impact on subsequent responsiveness to ethanol.

BACKGROUND: Recent evidence indicates that adolescent animals are more sensitive than adults to the disruptive effects of acute ethanol exposure on spatial learning. It is not yet known whether adolescent animals are also more sensitive than adults to the enduring neurobehavioral effects of repeated ethanol exposure. In this study, animals were exposed to ethanol in a binge-pattern during either adolescence or adulthood. At a time when all subjects were adults, spatial working memory was examined in the absence and presence of an acute ethanol challenge. METHODS: Rats were exposed to ethanol (5.0 g/kg intraperitoneally) or isovolumetric saline at 48 hr intervals over 20 days. Exposure began on either postnatal day 30 (adolescent group) or 70 (adult group). Twenty days after the final injection, a time at which all animals were adults, the subjects were tested on an elevated plus maze and then were trained to perform a spatial working memory task on an eight-arm radial maze. At the beginning of each session of training on the working memory task, subjects retrieved food rewards on four of the eight arms. After a delay, subjects were placed on the maze and allowed to retrieve food from the remaining four arms. RESULTS: Prior exposure to ethanol did not influence behavior on the plus maze. Performance of the groups did not differ during acquisition of the spatial working memory task with a 5 min delay or during subsequent testing with a 1 hr delay. However, animals treated with ethanol during adolescence exhibited larger working memory impairments during an ethanol challenge (1.5 g/kg intraperitoneally) than subjects in the other three groups. CONCLUSIONS: The findings indicate that binge pattern exposure to ethanol during adolescence enhances responsiveness to the memory-impairing effects of ethanol in adulthood.

Authors
White, AM; Ghia, AJ; Levin, ED; Swartzwelder, HS
MLA Citation
White, AM, Ghia, AJ, Levin, ED, and Swartzwelder, HS. "Binge pattern ethanol exposure in adolescent and adult rats: differential impact on subsequent responsiveness to ethanol." Alcohol Clin Exp Res 24.8 (August 2000): 1251-1256.
PMID
10968665
Source
pubmed
Published In
Alcoholism: Clinical and Experimental Research
Volume
24
Issue
8
Publish Date
2000
Start Page
1251
End Page
1256

Nicotinic treatment for degenerative neuropsychiatric disorders such as Alzheimer's disease and Parkinson's disease.

Nicotinic systems play an important role in the neural basis of working memory and attention. Recent progress in understanding of the structure, function, and distribution of central nervous system (CNS) nicotinic receptors and their pharmacology has opened up new possibilities for novel CNS therapeutics with nicotinic agents. In this paper, we review the theoretical justification and the experimental evidence supporting these developments. We focus on the applications of nicotinic agonists in CNS disorders that are degenerative in nature, namely Parkinson's disease and Alzheimer's disease. We suggest that there is considerable potential for therapeutic applications in the near future. Clinically, two major issues remain: (a) the selectivity of effects, that is, developing compounds which are selective in producing improvement in cognition, motor function, attention, or pain without significant side-effects; and (b) the realistic likelihood of long-term improvements in everyday functioning in people who have degenerative diseases.

Authors
Rusted, JM; Newhouse, PA; Levin, ED
MLA Citation
Rusted, JM, Newhouse, PA, and Levin, ED. "Nicotinic treatment for degenerative neuropsychiatric disorders such as Alzheimer's disease and Parkinson's disease." Behav Brain Res 113.1-2 (August 2000): 121-129. (Review)
PMID
10942039
Source
pubmed
Published In
Behavioural Brain Research
Volume
113
Issue
1-2
Publish Date
2000
Start Page
121
End Page
129

Rapid neurobehavioral analysis of Pfiesteria piscicida effects in juvenile and adult rats.

The estuarine dinoflagellate Pfiesteria piscicida is known to kill fish and has been associated with neurocognitive deficits in humans. We have developed a rat model to demonstrate that exposure to Pfiesteria causes significant learning impairments. This has been repeatedly seen as a choice accuracy impairment during radial-arm maze learning. Pfiesteria-induced effects were also seen in a locomotor activity test in the figure-8 apparatus. The current studies used the short-term radial-arm maze acquisition, the figure-8 activity test, and the functional observational battery (FOB) to assess Pfiesteria-induced neurobehavioral effects in adult and juvenile rats. In study 1, the neurobehavioral potency of three different Pfiesteria cultures (Pf 113, Pf 728, and Pf Vandermere) was assessed. Ninety-six (12 per group) adult female Sprague-Dawley rats were injected subcutaneously with a single dose of Pfiesteria taken from aquarium-cultured Pfiesteria (35,600 or 106,800 Pfiesteria cells per kilogram of rat body weight). One control group (N = 12) was injected with saline and one (N = 12) with aquarium water not containing Pfiesteria. All three of the Pfiesteria samples (p < 0.05) impaired choice accuracy over the first six sessions of training. At the time of the radial-arm maze choice accuracy impairment, no overt Pfiesteria-related effects were seen using an FOB, indicating that the Pfiesteria-induced choice accuracy deficit was not due to generalized debilitation. In the figure-8 apparatus, Pfiesteria treatment caused a significant decrease in mean locomotor activity. In study 2, the neurobehavioral effects of the Pf 728 sample type were assessed in juvenile rats. Twenty-four day-old male and female rats were injected with 35,600 or 106,800 Pf-728 Pfiesteria cells per kilogram of rat body weight. As with adult females, the juvenile rats showed a significant impairment in radial-arm maze choice accuracy. No changes in locomotor activity or the FOB were detected in the juvenile rats. Furthermore, there were no differences between male and female rats in the Pfiesteria-induced choice accuracy impairment. Pfiesteria effects on choice accuracy in the radial-arm maze in rats constitute a critical component of the model of Pfiesteria toxicity, because the hallmark of Pfiesteria toxicity in humans is cognitive dysfunction. Our finding that analysis of the first six sessions of radial-arm maze testing is sufficient for determining the effect means that this test will be useful as a rapid screen for identifying the critical neurotoxin(s) of Pfiesteria in future studies.

Authors
Levin, ED; Rezvani, AH; Christopher, NC; Glasgow, HB; Deamer-Melia, NJ; Burkholder, JM; Moser, VC; Jensen, K
MLA Citation
Levin, ED, Rezvani, AH, Christopher, NC, Glasgow, HB, Deamer-Melia, NJ, Burkholder, JM, Moser, VC, and Jensen, K. "Rapid neurobehavioral analysis of Pfiesteria piscicida effects in juvenile and adult rats." Neurotoxicol Teratol 22.4 (July 2000): 533-540.
PMID
10974591
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
22
Issue
4
Publish Date
2000
Start Page
533
End Page
540

Attention as a target of intoxication: insights and methods from studies of drug abuse.

A symposium was convened to discuss recent developments in the assessment of attention and the effects of drugs and toxic chemicals on attention at the 17th annual meeting of the Behavioral Toxicology Society on May 1, 1999, in Research Triangle Park, NC. Speakers addressed issues including the methodology of assessing cognitive function, the neurobiology of specific aspects of attention, the dual roles of attention as a target of intoxication and as a mediating variable in the development of addiction to psychoactive drugs, the changes in attention that accompany neuropsychological disorders of schizophrenia, senile dementia of the Alzheimer type and attention deficit hyperactivity disorder, and potential therapies for these disorders. This article provides an overview of the objectives of the symposium, followed by summaries of each of the talks given.

Authors
Bushnell, PJ; Levin, ED; Marrocco, RT; Sarter, MF; Strupp, BJ; Warburton, DM
MLA Citation
Bushnell, PJ, Levin, ED, Marrocco, RT, Sarter, MF, Strupp, BJ, and Warburton, DM. "Attention as a target of intoxication: insights and methods from studies of drug abuse." Neurotoxicol Teratol 22.4 (July 2000): 487-502. (Review)
PMID
10974587
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
22
Issue
4
Publish Date
2000
Start Page
487
End Page
502

Nicotine enhances stimulus detection performance of middle- and old-aged rats: a longitudinal study.

The effects of nicotine on sustained attention were tested in F344xBN male rats when they were chronologically middle and old aged. The rats (n = 11) were trained in a two-choice, stimulus detection task in which a press of one of two levers was reinforced with food, with the correct lever indicated by the position of a briefly illuminated light. They were tested when they were 24-25 and 34-35 months of age (i.e., at 60-68% and 85-95%, respectively of their expected median life span) after saline or 0.1-0.5 mg/kg doses of nicotine (SC). A significant dose-related improvement in percent correct choices and decrease in choice response times was found at both ages, and there was no significant main effect of age or an age by dose interaction. These results support the position that nicotine can enhance attentional processes in rats throughout their life span. Nicotine and other nicotinic agonists may have efficacy in the treatment of disorders such as Alzheimer's disease.

Authors
Grilly, DM; Simon, BB; Levin, ED
MLA Citation
Grilly, DM, Simon, BB, and Levin, ED. "Nicotine enhances stimulus detection performance of middle- and old-aged rats: a longitudinal study." Pharmacol Biochem Behav 65.4 (April 2000): 665-670.
PMID
10764920
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
65
Issue
4
Publish Date
2000
Start Page
665
End Page
670

Development of nicotinic drug therapy for cognitive disorders.

Nicotine, as well as other nicotinic drugs, may provide useful therapeutic treatment for a variety of cognitive impairments including those found in Alzheimer's disease, schizophrenia and attention deficit hyperactivity disorder (ADHD). We have found that nicotine skin patches significantly improve attentional performance in people with these disease states as well as normal nonsmoking adults. Animal models are critical for determining the neurobehavioral bases for nicotinic effects on cognitive function. We have found in lesion and local infusion studies with rats that the hippocampus is an important substrate for nicotinic effects on working memory function. Both alpha7 and alpha4beta2 nicotinic receptors in the hippocampus are involved. Further work has investigated the relationship of nicotinic systems with dopaminergic and glutaminergic systems in the basis of cognitive function. Nicotine has proven to be a useful prototypic compound for the family of nicotinic compounds. It produces cognitive improvements in both animal models and clinical populations. Recent work with more selective nicotinic receptor agonists and antagonists in animal models is providing important information concerning the neural mechanisms for nicotinic involvement in cognitive function and opening avenues for development of safe and effective nicotinic treatments for clinical use.

Authors
Levin, ED; Rezvani, AH
MLA Citation
Levin, ED, and Rezvani, AH. "Development of nicotinic drug therapy for cognitive disorders." Eur J Pharmacol 393.1-3 (March 30, 2000): 141-146.
PMID
10771007
Source
pubmed
Published In
European Journal of Pharmacology
Volume
393
Issue
1-3
Publish Date
2000
Start Page
141
End Page
146

Molecular overexpression of extracellular superoxide dismutase increases the dependency of learning and memory performance on motivational state.

Extracellular superoxide dismutase (EC-SOD) controls the availability of extracellular superoxide and appears to play a role in controlling intercellular signaling. In this role EC-SOD can have potent effects on neurobehavioral function. In previous studies, we have found that either over- or under-expression of EC-SOD in mice significantly impairs spatial learning on the radial-arm maze. In the current study, the neurobehavioral nature of the EC-SOD role in cognitive function was determined. EC-SOD overexpression altered the relationship between both learning and memory with motivational state. Mice were tested in the radial-arm maze under a high motivational state (22-24 hours of food restriction) or a low motivational state (4-6 hours of food restriction). Under a high motivational state, the EC-SOD overexpressing mice were able to learn in the radial-arm maze, albeit at a slightly lower rate than wild-type controls. This contrasts with the failure to learn by EC-SOD overexpressing mice in our previous study conducted with the low motivational state. The change in motivational state did not significantly alter the learning rate of controls. Similarly, during postacquisition memory phase of testing, the EC-SOD overexpressing mice were significantly worse than controls when tested in a low motivational state but not under a high motivation state. As with learning, motivational state did not significantly affect memory performance in controls. This study shows that mice with EC-SOD overexpression are not incapable of learning and memory in the radial-arm maze, but that the mechanisms which allow control animals to perform this task well under low motivational states are deficient in the mice with EC-SOD overexpression.

Authors
Levin, ED; Brucato, FH; Crapo, JD
MLA Citation
Levin, ED, Brucato, FH, and Crapo, JD. "Molecular overexpression of extracellular superoxide dismutase increases the dependency of learning and memory performance on motivational state." Behav Genet 30.2 (March 2000): 95-100.
PMID
10979599
Source
pubmed
Published In
Behavior Genetics
Volume
30
Issue
2
Publish Date
2000
Start Page
95
End Page
100

AR-R17779, and alpha7 nicotinic agonist, improves learning and memory in rats.

Nicotinic acetylcholine systems have been found to be important for learning and memory function. The prototypic nicotinic agonist nicotine has been shown in a variety of studies to improve aspects of cognitive function. The specific involvement of nicotinic receptor subtypes is now being investigated. The involvement of alpha7 nicotinic receptors was assessed in this project using a novel alpha7 nicotinic agonist, AR-R 17779. Repeated doses (subcutaneous injection 20 min before testing) of the racemic mixture AR-R 13489 and its active isomer AR-R 17779 were assessed in adult female Sprague-Dawley rats using the eight-arm radial maze. AR-R 13489 (2 mg/kg) caused a significant improvement of long-term win-shift acquisition after 3 weeks of training (n = 10 per group). The same dose of AR-R 17779 also caused a significant improvement in repeated acquisition within each daily session in the radial-arm maze. In another study, the active isomer AR-R 17779 significantly improved radial-arm maze working memory function in rats with lesions to the septohippocampal projection. Fimbria-fornix lesions significantly impaired working memory performance and AR-R 17779 significantly reversed that impairment. These studies showed that alpha7 nicotinic agonist treatment improved learning in two radial-arm maze tasks and reversed working memory impairment caused by fimbria-fornix sections, providing evidence for alpha7 involvement in learning and memory, and the potential therapeutic use of AR-R 17779.

Authors
Levin, ED; Bettegowda, C; Blosser, J; Gordon, J
MLA Citation
Levin, ED, Bettegowda, C, Blosser, J, and Gordon, J. "AR-R17779, and alpha7 nicotinic agonist, improves learning and memory in rats." Behav Pharmacol 10.6-7 (November 1999): 675-680.
PMID
10780509
Source
pubmed
Published In
Behavioural Pharmacology
Volume
10
Issue
6-7
Publish Date
1999
Start Page
675
End Page
680

Pfiesteria toxin and learning performance.

Pfiesteria piscicida is an estuarine dinoflagellate involved with fish kills along the east coast of the United States. We previously documented a radial-arm maze learning deficit in rats exposed to Pfiesteria that may be related to cognitive deficits seen in humans after accidental Pfiesteria exposure. The current study elucidated important behavioral parameters of this deficit. There were six dose groups. Forty (10/group) adult female Sprague-Dawley rats were injected (s.c.) with a single dose of Pfiesteria taken from aquarium-cultured Pfiesteria (35,600, 106,800, or 320,400 Pfiesteria cells/kg of rat body weight or a cell-free filtrate of the 106,800 cells/kg dose). One control group (N = 10) was injected with saline and one (N = 10) with aquarium water not containing Pfiesteria. Half of the rats in each group were tested on an 8-arm radial maze in a standard test room, and the other half were tested on the radial maze in a sound-attenuating chamber. In the standard maze room, there was a significant effect of Pfiesteria (p < 0.05) impairing choice accuracy improvement over the first six sessions of training among rats administered 106,800, 320,400, and the 106,800 cells/kg filtered sample. In contrast, there was no indication of an effect of Pfiesteria when the rats were tested on the same configuration radial maze in the sound-attenuating chamber. After 18 sessions of training in one room, the rats were switched for six sessions of testing in the other room and finally were switched back to their original room for three sessions. There was a significant Pfiesteria-induced deficit when the rats were tested in the standard test room but not when they were tested in the sound-attenuating chamber. When the Pfiesteria-exposed rats were initially switched from the sound-attenuating chamber to the standard test room they performed significantly worse than controls, whereas Pfiesteria-treated rats switched from the standard test room to the sound-attenuating chamber did not perform differently from controls. These results suggest that the Pfiesteria-induced learning impairment may result from the negative impact of distracting stimuli. At the time of the learning impairment, no overt Pfiesteria-related effects were seen using a functional observational battery and no overall response latency effects were seen, indicating that the Pfiesteria-induced choice accuracy deficit was not due to generalized debilitation. In the initial use of the figure-8 maze in this line of research, the rats in the same Pfiesteria treatment groups that showed significant deficits in the radial-arm maze showed greater declines in activity rates in a 1-h figure-8 locomotor activity test. Both the 106,800 and 320,400 Pfiesteria cells/kg groups showed significantly greater linear trends of activity decline relative to tank water-treated controls. This reflected an initial slight hyperactivity in the Pfiesteria-treated animals followed by a decrease to control levels. Pfiesteria effects in the figure-8 maze and in early radial-arm maze training may be useful in a rapid screen for identifying the critical toxin(s) of Pfiesteria in future studies.

Authors
Levin, ED; Simon, BB; Schmechel, DE; Glasgow, HB; Deamer-Melia, NJ; Burkholder, JM; Moser, VC; Jensen, K; Harry, GJ
MLA Citation
Levin, ED, Simon, BB, Schmechel, DE, Glasgow, HB, Deamer-Melia, NJ, Burkholder, JM, Moser, VC, Jensen, K, and Harry, GJ. "Pfiesteria toxin and learning performance." Neurotoxicol Teratol 21.3 (May 1999): 215-221.
PMID
10386824
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
21
Issue
3
Publish Date
1999
Start Page
215
End Page
221

Nicotine and/or cocaine alters postnatal ventilatory control in the rat pup gestationally exposed

Authors
Gingras, JL; Leatherman, NE; Cutler, AR; Levin, ED
MLA Citation
Gingras, JL, Leatherman, NE, Cutler, AR, and Levin, ED. "Nicotine and/or cocaine alters postnatal ventilatory control in the rat pup gestationally exposed." PEDIATRIC RESEARCH 45.4 (April 1999): 51A-51A.
Source
wos-lite
Published In
Pediatric Research
Volume
45
Issue
4
Publish Date
1999
Start Page
51A
End Page
51A

Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer's disease.

RATIONALE: Acute nicotine injections have been found to improve attentional performance in patients with Alzheimer's disease (AD), but little is known about chronic nicotine effects. OBJECTIVE: The present study was undertaken to evaluate the clinical and neuropsychological effects of chronic transdermal nicotine in Alzheimer's disease subjects over a 4-week period. METHODS: The double-blind, placebo controlled, cross-over study consisted of two 4-week periods separated by a 2-week washout period. Patients wore the nicotine patch (Nicotrol) for 16 h a day at the following doses: 5 mg/day during week 1, 10 mg/day during weeks 2 and 3 and 5 mg/day during week 4. The eight subjects had mild to moderate AD and were otherwise healthy. RESULTS: Nicotine significantly improved attentional performance as measured by the Conners' continuous performance test (CPT). There was a significant reduction in errors of omission on the CPT which continued throughout the period of chronic nicotine administration. The variability of hit reaction time (reaction time for correct responses) on the CPT was also significantly reduced by chronic nicotine. Nicotine did not improve performance on other tests measuring motor and memory function. CONCLUSIONS: The sustained improvement in attention found in this study with nicotine dermal patches is encouraging. However, the lack of detected effects of nicotine treatment on other cognitive and behavioral domains in this study leaves questions concerning the clinical impact of nicotinic treatment in Alzheimer's disease. The modest size of this study limited statistical power which may have been needed to detect more subtle but clinically significant cognitive effects. Higher doses of nicotine, other nicotinic ligands or combination treatment of nicotine with other therapies may be efficacious for producing broader therapeutic effects.

Authors
White, HK; Levin, ED
MLA Citation
White, HK, and Levin, ED. "Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer's disease." Psychopharmacology (Berl) 143.2 (April 1999): 158-165.
PMID
10326778
Source
pubmed
Published In
Psychopharmacology
Volume
143
Issue
2
Publish Date
1999
Start Page
158
End Page
165

Ventral hippocampal dopamine D1 and D2 systems and spatial working memory in rats.

The hippocampus has long been known to be important for memory function. However, the involvement of hippocampal dopamine systems with memory has received little attention. In the current study, dopamine D1 and D2 hippocampal receptor system involvement with memory was assessed in female Sprague-Dawley rats by local infusion of D1 and D2 agonists and antagonists into the ventral hippocampus. Working memory performance was assessed on the radial-arm maze. Neither the D1 agonist dihydrexidine (1.1-10 microg/side) nor the D1 antagonist SCH 23390 (0.19-1.67 microg/side) was effective in significantly altering radial-arm maze choice accuracy. In contrast, there were significant and opposite effects of D2 agonist and antagonist treatments. The D2 agonist quinpirole caused a significant (P<0.05) dose-related improvement in choice accuracy over a dose range of 1.1-10 microg/side. In a complementary fashion, the D2 antagonist raclopride caused a significant (P<0.05) dose-related choice accuracy deficit over a range of 0.19-1.67 microg/side. This study provides clear evidence that hippocampal D2 activity is positively related to working memory performance, while evidence for D1 systems is less compelling. Dopamine D2 receptors in the ventral hippocampus were shown to have important influences on spatial working memory. In a consistent pattern of effects ventral hippocampal infusion of the D2 agonist quinpirole improved working memory performance in the radial-arm maze, while ventral hippocampal infusion of the D2 antagonist raclopride impaired performance.

Authors
Wilkerson, A; Levin, ED
MLA Citation
Wilkerson, A, and Levin, ED. "Ventral hippocampal dopamine D1 and D2 systems and spatial working memory in rats." Neuroscience 89.3 (March 1999): 743-749.
PMID
10199609
Source
pubmed
Published In
Neuroscience
Volume
89
Issue
3
Publish Date
1999
Start Page
743
End Page
749

Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity.

The mechanism by which psychostimulants act as calming agents in humans with attention-deficit hyperactivity disorder (ADHD) or hyperkinetic disorder is currently unknown. Mice lacking the gene encoding the plasma membrane dopamine transporter (DAT) have elevated dopaminergic tone and are hyperactive. This activity was exacerbated by exposure to a novel environment. Additionally, these mice were impaired in spatial cognitive function, and they showed a decrease in locomotion in response to psychostimulants. This paradoxical calming effect of psychostimulants depended on serotonergic neurotransmission. The parallels between the DAT knockout mice and individuals with ADHD suggest that common mechanisms may underlie some of their behaviors and responses to psychostimulants.

Authors
Gainetdinov, RR; Wetsel, WC; Jones, SR; Levin, ED; Jaber, M; Caron, MG
MLA Citation
Gainetdinov, RR, Wetsel, WC, Jones, SR, Levin, ED, Jaber, M, and Caron, MG. "Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity." Science 283.5400 (January 15, 1999): 397-401.
PMID
9888856
Source
pubmed
Published In
Science
Volume
283
Issue
5400
Publish Date
1999
Start Page
397
End Page
401

Ventral hippocampal ibotenic acid lesions block chronic nicotine-induced spatial working memory improvement in rats.

Chronic nicotine infusions have been found to significantly improve working memory performance in the radial-arm maze. This effect is blocked by co-infusions of the nicotinic antagonist mecamylamine. Acute nicotine injections also improve working memory performance in the radial-arm maze. This effect is also blocked by mecamylamine co-administration. Recent local infusions studies have demonstrated the importance of the ventral hippocampus for nicotinic involvement in memory. Local infusions of mecamylamine, DHbetaE or MLA impair working memory performance on the radial-arm maze. The current study was conducted to determine the importance of the ventral hippocampus for the chronic effects of nicotine. Rats were trained on the working memory task in an eight-arm radial maze. After acquisition they underwent either infusions of ibotenic acid lesions or vehicle infusions and received subcutaneous implants of osmotic minipumps that delivered either nicotine at a dose of 5 mg kg-1 day-1 or vehicle in a 2x2 design. The rats then were given 2 days of recovery and were tested on the radial-arm maze three times per week for the next 4 weeks. As seen in previous studies, in the sham lesioned group nicotine infusions caused a significant improvement in choice accuracy. In contrast no nicotine-induced improvement was seen in the rats after ibotenic acid lesions of the ventral hippocampus. The effect of nicotine was blocked even though this lesion did not cause a deficit in performance. Previous work showed that chronic nicotine infusion still caused a significant improvement in working memory performance in the radial-arm maze after knife-cut lesions of the fimbria-fornix carrying the septo-hippocampal cholinergic innervation. Thus it appears that it is the postsynaptic nicotinic receptors in the ventral hippocampus which are critically important for the expression of the chronic nicotine induced working memory improvement.

Authors
Levin, ED; Christopher, NC; Weaver, T; Moore, J; Brucato, F
MLA Citation
Levin, ED, Christopher, NC, Weaver, T, Moore, J, and Brucato, F. "Ventral hippocampal ibotenic acid lesions block chronic nicotine-induced spatial working memory improvement in rats." Brain Res Cogn Brain Res 7.3 (January 1999): 405-410.
PMID
9838204
Source
pubmed
Published In
Cognitive Brain Research
Volume
7
Issue
3
Publish Date
1999
Start Page
405
End Page
410

Assessment of immunotoxicology in wild populations: Review and recommendations

A heightened recognition of the immunotoxicity of many xenobiotics has sparked increased interest in studying immune system effects in wildlife. Immunotoxicological endpoints have been directly informative in assessing the health of wildlife populations themselves, and wildlife could also potentially be used as indicators of human and ecosystem health. However, the lack of standard methods and information regarding normal ranges of immune system parameters makes field assessments of wildlife immunological status difficult. Compounding this difficulty is the unfamiliarity of most wildlife toxicologists with the complex immune system and the wide array of methods available to study immunotoxicity. This restricts the number of studies carried out and further limits the growth of a wildlife immunological database. The purpose of this review is to facilitate the study of immunological endpoints by wildlife toxicologists by presenting 1) an overview of immunotoxicology from a biomedical perspective with an emphasis on the fundamentals of the immune system and the tools/assays available for measuring its function; 2) a limited review of applied immunotoxicity studies in wild fish, birds, and mammals; and 3) recommendations for expanding immunological assessments in wildlife.

Authors
Keller, JM; Meyer, JN; Mattie, M; Augspurger, T; Rau, M; Dong, J; Levin, ED
MLA Citation
Keller, JM, Meyer, JN, Mattie, M, Augspurger, T, Rau, M, Dong, J, and Levin, ED. "Assessment of immunotoxicology in wild populations: Review and recommendations." Reviews in Toxicology 3.1-4 (1999): 167-212.
Source
scival
Published In
Reviews in Toxicology
Volume
3
Issue
1-4
Publish Date
1999
Start Page
167
End Page
212

Bridged nicotine, isonicotine, and norisonicotine effects on working memory performance of rats in the radial-arm maze

Nicotine and other nicotinic agonists have been found tO improve performance in a variety of tasks, including the radial-arm maze to improve memory. There has been an active effort to develop novel nicotinic agonists for the treatment of cognitive dysfunction such as is seen in Alzheimer's disease. These novel ligands can also serve as tools with which to increase our knowledge concerning the involvement of nicotinic systems with cognitive function. The current studies were conducted to assess the actions of three new nicotinic agonists, i.e., bridged nicotine, isonicotine, and norisonicotine, on choice accuracy in the radial-arm maze. Rats were trained on a win-shift working memory task in the eight-arm radial maze. In Experiment 1, the rats were administered (subcutaneously) saline and three doses of bridged nicotine, isonicotine, and norisonicotine (0.5, 1.5, and 4.5 mg/kg). Bridged nicotine did not cause any significant effects on memory performance, although it did significantly increase latency and at the high dose caused severe slowing and nonperformance. Both isonicotine and norisonicotine caused a significant linear dose-related improvement in choice accuracy, indicative of improved working memory function. In Experiment 2, another set of rats received the effective doses of 4.5 mg/kg of isonicotine and norisonicotine as well as higher doses of 13.5 mg/kg of each compound. These doses were administered alone or in combination with 5 mg/kg of the nicotinic antagonist mecamylamine to determine the nicotinic nature of the effects. As in Experiment 1 the 4.5 mg/kg of isonicotine caused a significant memory improvement. The 4.5 mg/kg dose of norisonicotine caused a more modest rise in performance, which was not significantly different from control in this experiment. When both experiments were considered together, the 4.5 mg/kg doses of both isonicotine and norisonicotine were the most effective in improving working memory performance. Significant improvements in working memory were seen with both drugs (P < 0.025). The higher doses of 13.5 mg/kg of both isonicotine and norisonicotine resulted in nearly control-level performance. Thus, the typical inverted U-shaped dose-effect function was evident for both isonicotine and norisonicotine. Mecamylamine brought performance improved by the 4.5 mg/kg dose back to control levels, providing evidence for the nicotinic nature of the effect. Both isonicotine and norisonicotine show promise for development as memory-improving nicotinic agonist drugs.

Authors
Levin, ED; Damaj, MI; Glassco, W; May, EL; Martin, BR
MLA Citation
Levin, ED, Damaj, MI, Glassco, W, May, EL, and Martin, BR. "Bridged nicotine, isonicotine, and norisonicotine effects on working memory performance of rats in the radial-arm maze." Drug Development Research 46.2 (1999): 107-111.
Source
scival
Published In
Drug Development Research
Volume
46
Issue
2
Publish Date
1999
Start Page
107
End Page
111
DOI
10.1002/(SICI)1098-2299(199902)46:2<107::AID-DDR3>3.0.CO;2-C

Mutually potentiating effects of mecamylamine and haloperidol in producing catalepsy in rats

Haloperidol and other dopaminergic (DA) blockers have long been known to induce catalepsy. Recently, it has been reported that nicotine potentiates the cataleptic effect of haloperidol. However, this presents a quandary in terms of neural interactions between nicotinic and DA systems. Nicotine promotes the release of DA in the striatum, which should attenuate haloperidol-induced catalepsy. To resolve this quandary, we assessed haloperidol interactions with nicotine and its antagonist mecamylamine in five studies. With low to moderate doses, we did not find that nicotine potentiated haloperidol-induced catalepsy. However, in two different studies we found that mecamylamine, a nicotinic antagonist, significantly potentiated the haloperidol-induced catalepsy. This effect was seen with a dose of mecamylamine which, by itself, did not have any cataleptic effect. These results demonstrate that nicotinic receptor blockade effectively potentiates catalepsy caused by DA blockade. This suggests that previously seen nicotine- induced potentiation of catalepsy may have been due to its desensitizing effect. Perhaps the use of nicotinic antagonists such as mecamylamine or nicotine + mecamylamine combinations would provide a useful adjunct to DA antagonist therapy in motor disorders such as Tourette's syndrome.

Authors
Levin, ED; Lippiello, P
MLA Citation
Levin, ED, and Lippiello, P. "Mutually potentiating effects of mecamylamine and haloperidol in producing catalepsy in rats." Drug Development Research 47.2 (1999): 90-96.
Source
scival
Published In
Drug Development Research
Volume
47
Issue
2
Publish Date
1999
Start Page
90
End Page
96
DOI
10.1002/(SICI)1098-2299(199906)47:2<90::AID-DDR4>3.0.CO;2-5

Transdermal nicotine effects on attention.

Nicotine has been shown to improve attentiveness in smokers and attenuate attentional deficits in Alzheimer's disease patients, schizophrenics and adults with attention-deficit/hyperactivity disorder (ADHD). The current study was conducted to determine whether nicotine administered via transdermal patches would improve attentiveness in non-smoking adults without attentional deficits. The subjects underwent the nicotine and placebo exposure in a counterbalanced double-blind manner. Measures of treatment effect included the Profile of Mood States (POMS), Conners' computerized Continuous Performance Test (CPT) of attentiveness and a computerized interval-timing task. The subjects were administered a 7 mg/day nicotine transdermal patch for 4.5 h during a morning session. Nicotine significantly increased self-perceived vigor as measured by the POMS test. On the CPT, nicotine significantly decreased the number of errors of omission without causing increases in either errors of commission or correct hit reaction time. Nicotine also significantly decreased the variance of hit reaction time and the composite measure of attentiveness. This study shows that, in addition to reducing attentional impairment, nicotine administered via transdermal patches can improve attentiveness in normal adult non-smokers.

Authors
Levin, ED; Conners, CK; Silva, D; Hinton, SC; Meck, WH; March, J; Rose, JE
MLA Citation
Levin, ED, Conners, CK, Silva, D, Hinton, SC, Meck, WH, March, J, and Rose, JE. "Transdermal nicotine effects on attention." Psychopharmacology (Berl) 140.2 (November 1998): 135-141.
PMID
9860103
Source
pubmed
Published In
Psychopharmacology
Volume
140
Issue
2
Publish Date
1998
Start Page
135
End Page
141

Nicotine-dizocilpine interactions and working and reference memory performance of rats in the radial-arm maze.

Both nicotinic cholinergic and NMDA glutaminergic systems are important for memory function. Nicotine has been found repeatedly to significantly improve working memory performance in the radial-arm maze. The NMDA antagonist dizocilpine has been found to impair working memory performance. There is neuropharmacological evidence that these two systems are functionally related. Nicotine is potent at releasing many transmitters including glutamate. The current study was conducted to examine the interaction of nicotinic and NMDA systems with regard to working and reference memory. Rats were trained on a working/reference procedure on a 16-arm radial maze. After acquisition, they were administered nicotine (0, 0.2, and 0.4 mg/kg) and dizocilpine (0, 100, and 200 microg/kg) alone or in combination in a repeated measures, counterbalanced design. As seen previously, nicotine at a dose of 0.2 mg/kg caused a significant improvement in working but not reference memory performance in the radial-arm maze. The 200 microg/kg dose of dizocilpine made the rats nonresponsive on the maze so that choice accuracy could not be assessed. The 100 microg/kg dose of dizocilpine caused significant impairments in both working and reference memory. The 0.4 mg/kg dose of nicotine significantly attenuated the dizocilpine-induced deficit in both working and reference memory. NMDA blockade impairs working and reference memory and blocks the expression of the working memory improvement caused by 0.2 mg/kg of nicotine. However, a higher dose of 0.4 mg/kg of nicotine is effective at attenuating the dizocilpine-induced deficit, even though this dose alone is not effective in improving performance. A second study examined the effects of a lower dose range of dizocilpine. Comensurately smaller memory impairments were seen with lower doses of dizocilpine down to 12.5 microg/kg, which did not produce any significant effects on memory performance or response latency. Nicotine had a more modest effect in attenuating the smaller deficits caused by these lower doses of dizocilpine. These studies provide evidence for important interactions between nicotinic and NMDA systems with regard to memory function.

Authors
Levin, ED; Bettegowda, C; Weaver, T; Christopher, NC
MLA Citation
Levin, ED, Bettegowda, C, Weaver, T, and Christopher, NC. "Nicotine-dizocilpine interactions and working and reference memory performance of rats in the radial-arm maze." Pharmacol Biochem Behav 61.3 (November 1998): 335-340.
PMID
9768569
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
61
Issue
3
Publish Date
1998
Start Page
335
End Page
340

Molecular manipulations of extracellular superoxide dismutase: functional importance for learning.

Extracellular superoxide dismutase (EC-SOD) controls the availability of extracellular superoxide (O2.-), which is important for a variety of physiological pathways, including the primary means of inactivating nitric oxide (NO). The role of EC-SOD in neurobehavioral function has been until now unexplored. In the current studies, the phenotypic expression of genotypic alterations of EC-SOD production in mice were characterized for spatial learning and memory. Dramatic impairments in spatial learning in the win-shift 8-arm radial maze were seen in both EC-SOD knockout mice and EC-SOD overexpressing mice. The EC-SOD overexpressing mice were further characterized as having significant deficits in a repeated acquisition task in the radial-arm maze, which permitted the dissociation of long and short-term learning. Long-term learning was significantly impared by EC-SOD overexpression, whereas short-term learning was not significantly affected by EC-SOD overexpression. No systems have been shown to be importantly involved in learning and memory. This may be important in the current studies because EC-SOD has primary control over the inactivation of NO. We found that EC-SOD overexpressing mice were resistant to the cognitive effects of L-NAME (NG-nitro-L-arginine methyl ester hydrochloride), an NO synthase inhibitor. Decreased NO catabolism in these mice may have served to counter the effects of NOS inhibition by L-NAME. The current finding that EC-SOD levels that were either higher or lower than controls impaired learning demonstrates that the proper control of brain extracellular O2.- may be more vital than merely reduction of brain extracellular O2.- in maintaining adequate learning function.

Authors
Levin, ED; Brady, TC; Hochrein, EC; Oury, TD; Jonsson, LM; Marklund, SL; Crapo, JD
MLA Citation
Levin, ED, Brady, TC, Hochrein, EC, Oury, TD, Jonsson, LM, Marklund, SL, and Crapo, JD. "Molecular manipulations of extracellular superoxide dismutase: functional importance for learning." Behav Genet 28.5 (September 1998): 381-390.
PMID
9926619
Source
pubmed
Published In
Behavior Genetics
Volume
28
Issue
5
Publish Date
1998
Start Page
381
End Page
390

Nicotinic acetylcholine involvement in cognitive function in animals.

Nicotinic cholinergic systems are involved with several important aspects of cognitive function including attention, learning and memory. Nicotinic cholinergic receptors are located in many regions of the brain, including areas important for cognitive function such as the hippocampus and frontal cortex. Nicotinic agonists have been found in rodent and non-human primate studies to improve performance on a variety of memory tasks. In a complementary fashion, nicotinic antagonists such as mecamylamine impair working memory function. In humans, similar effects have been seen. Nicotinic agonist treatment can improve attention, learning and memory and nicotinic antagonist treatment can cause deficits. To define the neural substrates of nicotinic involvement in cognitive function, three areas of investigation are underway. 1) Critical neuroanatomic loci for nicotinic effects are beginning to be determined. The hippocampus, frontal cortex and midbrain dopaminergic nuclei have been found to be important sites of action for nicotinic involvement in memory function. 2) Nicotinic receptor subtype involvement in cognitive function is being studied. There has been considerable recent work identifying nicotinic receptor subunit conformation including alpha and beta subunits. Nicotinic receptor subtypes appear to be associated with different functional systems; however, much remains to be done to determine the precise role each subtype plays in terms of cognitive function. 3) Nicotinic interactions with other transmitter systems are being assessed. Nicotine receptors interact in important ways with other systems to affect cognitive functioning, including muscarinic ACh, dopamine, norepinepherine, serotonin, glutamate, and other systems. Nicotinic function in clinical populations and potential for therapeutics has been investigated for Alzheimer's disease, Parkinson's disease, schizophrenia and attention deficit/hyperactivity disorder. Areas which need to receive greater attention are the exact anatomical location and the specific receptor subtypes critically involved in nicotine's effects. In addition, more work needs to be done to develop and determine the efficacy and safety of novel nicotinic ligands for use in the long-term treatment of human cognitive disorders.

Authors
Levin, ED; Simon, BB
MLA Citation
Levin, ED, and Simon, BB. "Nicotinic acetylcholine involvement in cognitive function in animals." Psychopharmacology (Berl) 138.3-4 (August 1998): 217-230. (Review)
PMID
9725745
Source
pubmed
Published In
Psychopharmacology
Volume
138
Issue
3-4
Publish Date
1998
Start Page
217
End Page
230

Oxidative stress in toxicology: established mammalian and emerging piscine model systems.

Interest in the toxicological aspects of oxidative stress has grown in recent years, and research has become increasingly focused on the mechanistic aspects of oxidative damage and cellular responses in biological systems. Toxic consequences of oxidative stress at the subcellular level include lipid peroxidation and oxidative damage to DNA and proteins. These effects are often used as end points in the study of oxidative stress. Typically, mammalian species have been used as models to study oxidative stress and to elucidate the mechanisms underlying cellular damage and response, largely because of the interest in human health issues surrounding oxidative stress. However, it is becoming apparent that oxidative stress also affects aquatic organisms exposed to environmental pollutants. Research in fish has demonstrated that mammalian and piscine systems exhibit similar toxicological and adaptive responses to oxidative stress. This suggests that piscine models, in addition to traditional mammalian models, may be useful for further understanding the mechanisms underlying the oxidative stress response.

Authors
Kelly, KA; Havrilla, CM; Brady, TC; Abramo, KH; Levin, ED
MLA Citation
Kelly, KA, Havrilla, CM, Brady, TC, Abramo, KH, and Levin, ED. "Oxidative stress in toxicology: established mammalian and emerging piscine model systems." Environ Health Perspect 106.7 (July 1998): 375-384. (Review)
PMID
9637794
Source
pubmed
Published In
Environmental health perspectives
Volume
106
Issue
7
Publish Date
1998
Start Page
375
End Page
384

Long-term neuroprotection by benzodiazepine full versus partial agonists after transient cerebral ischemia in the gerbil [corrected].

The ability of diazepam, a benzodiazepine full agonist, and imidazenil, a benzodiazepine partial agonist, to protect hippocampal area CA1 neurons from death for at least 35 days after cerebral ischemia was investigated. Diazepam (10 mg/kg) administered to gerbils 30 and 90 minutes after forebrain ischemia produced significant protection of hippocampal area CA1 pyramidal neurons 7 days later. In gerbils surviving for 35 days, diazepam produced the same degree of neuroprotection (70% +/- 30%) in the hippocampus compared with 7 days after ischemia. The therapeutic window for diazepam was short; there was no significant neuroprotection when the administration of diazepam was delayed to 4 hours after ischemia. The neuroprotective dose of diazepam also produced hypothermia (approximately 32 degrees C) for several hours after injection. To assess the role of hypothermia in neuroprotection by diazepam, hypothermia depth and duration was simulated using a cold-water spray in separate gerbils. Seven days after ischemia, neuroprotection by hypothermia was similar to that produced by diazepam. However, 35 days after ischemia, there was no significant protection by hypothermia, suggesting that hypothermia does not play a significant role in long-term diazepam neuroprotection. Imidazenil (3 mg/kg), which produced only minimal hypothermia, protected area CA1 of hippocampus to the same degree as that by diazepam 7 days after ischemia. At 35 days after ischemia, significant protection remained, but it was considerably reduced compared with 7 days. Like diazepam, the therapeutic window for imidazenil was short. Imidazenil neuroprotection was lost when the drug was administered as early as 2 hours after ischemia. The ability of ischemia to produce deficits in working memory and of benzodiazepines to prevent the deficits also was investigated. Gerbils trained on an eight-arm radial maze before ischemia demonstrated a significant increase in the number of working errors 1 month after ischemia. The ischemia-induced deficits in working memory were completely prevented by diazepam but not by imidazenil. There was a significant, but weak, negative correlation between the degree of CA1 pyramidal cell survival and the number of working errors in both the diazepam and imidazenil groups. Thus, if given early enough during reperfusion, both benzodiazepine full and partial agonists are neuroprotective for at least 35 days, but the lack of sedating side effects of imidazenil must be weighed against its reduced efficacy.

Authors
Schwartz-Bloom, RD; McDonough, KJ; Chase, PJ; Chadwick, LE; Inglefield, JR; Levin, ED
MLA Citation
Schwartz-Bloom, RD, McDonough, KJ, Chase, PJ, Chadwick, LE, Inglefield, JR, and Levin, ED. "Long-term neuroprotection by benzodiazepine full versus partial agonists after transient cerebral ischemia in the gerbil [corrected]." J Cereb Blood Flow Metab 18.5 (May 1998): 548-558.
PMID
9591847
Source
pubmed
Published In
Journal of Cerebral Blood Flow and Metabolism
Volume
18
Issue
5
Publish Date
1998
Start Page
548
End Page
558
DOI
10.1097/00004647-199805000-00010

Differential effects of ethanol on memory in adolescent and adult rats.

Previous studies have shown that ethanol inhibits memory-related synaptic activity and plasticity more potently in hippocampal slices from immature rats, compared with those taken from adults. We therefore hypothesized that ethanol would more potently attenuate the acquisition of spatial memory in adolescents, compared with adult rats. Adult (65 days of age) and adolescent (30 days of age) male rats were given five daily trials on a spatial memory task in a Morris Water Maze. The animals from each age group were subdivided into three subgroups. Each day, thirty minutes before training, the animals in each subgroup were given an intraperitoneal injection of 1.0 g/kg of ethanol, 2.0 g/kg of ethanol, or the saline vehicle. Training continued daily until the control animals had reached a performance criterion. Ethanol treatment significantly impaired spatial memory acquisition in the adolescent rats, but did not impair acquisition in adult rats. A separate experiment with identical treatment groups showed that ethanol did not impair acquisition of a nonspatial memory task in the water maze in animals from either age group. These experiments show that the acquisition of spatial, but not nonspatial, memory is more potently impaired by ethanol in adolescent animals, compared with adults.

Authors
Markwiese, BJ; Acheson, SK; Levin, ED; Wilson, WA; Swartzwelder, HS
MLA Citation
Markwiese, BJ, Acheson, SK, Levin, ED, Wilson, WA, and Swartzwelder, HS. "Differential effects of ethanol on memory in adolescent and adult rats." Alcohol Clin Exp Res 22.2 (April 1998): 416-421.
PMID
9581648
Source
pubmed
Published In
Alcoholism: Clinical and Experimental Research
Volume
22
Issue
2
Publish Date
1998
Start Page
416
End Page
421

Nicotinic antagonist administration into the ventral hippocampus and spatial working memory in rats.

Nicotinic acetylcholine receptors are important for maintaining optimal memory performance. In order to more fully characterize the involvement of nicotinic systems in memory, the contributions of nicotinic acetylcholine receptor subtypes were investigated. This study targeted the alpha 7 and alpha 4 beta 2 nicotinic receptors in the ventral hippocampus, an area known to be important for spatial working memory. Antagonists of alpha 7 and alpha 4 beta 2 receptors were locally infused into the ventral hippocampus of rats and the effects on memory were examined with the radial-arm maze. The subtype-specific competitive antagonists infused into separate groups of rats were methyllycaconitine citrate (an alpha 7 antagonist) and dihydro-beta-erythroidine hydrobromide (an alpha 4 beta 2 antagonist). Their effects on radial-arm maze performance were contrasted with the non-specific competitive antagonist, D-tubocurarine chloride. Significant deficits in radial-arm maze choice accuracy performance were found at 78.7 micrograms/side for methyllycaconitine and at 106.9 micrograms/side for dihydro-beta-erythroidine. Increased response latency was also seen at these doses. Tubocurarine induced seizures at doses previously reported to have no effect. Wet dog shakes were seen in most rats at 0.1 microgram/side with tubocurarine, 26.3 micrograms/side with methyllycaconitine and 106.9 micrograms/side with dihydro-beta-erythroidine. This study suggests that both alpha 7 and alpha 4 beta 2 nicotinic acetylcholine receptor subtypes are involved in working memory formation and that the hippocampus is a critical site for nicotinic cholinergic involvement in memory function, though the high doses of antagonists needed to produce the memory impairment may have had less than completely specific effects.

Authors
Felix, R; Levin, ED
MLA Citation
Felix, R, and Levin, ED. "Nicotinic antagonist administration into the ventral hippocampus and spatial working memory in rats." Neuroscience 81.4 (December 1997): 1009-1017.
PMID
9330363
Source
pubmed
Published In
Neuroscience
Volume
81
Issue
4
Publish Date
1997
Start Page
1009
End Page
1017

Chronic haloperidol administration does not block acute nicotine-induced improvements in radial-arm maze performance in the rat.

Nicotine has been found to improve cognitive performance in a variety of tasks including the radial maze. Nicotine has also been shown to promote the release of a variety of neurotransmitters including dopamine (DA). DA has been found to be important for nicotine's reinforcing effects. DA involvement with nicotine's cognitive effects is unclear. In the current study, the effects of acute nicotine injections (0, 0.1, 0.2, or 0.4 mg/kg) were examined on radial-arm maze performance in rats given chronic infusions the DA antagonist haloperidol (0, 0.2, or 0.6 mg/kg/day). Chronic haloperidol infusion was not found to attenuate the memory improvement caused by acute nicotine injection. In fact, the dose-related nicotine-induced memory improvement was clearer in the haloperidol-treated groups than in controls. This is similar to the effect of nicotine we saw in human subjects given chronic doses of haloperidol. Our previous studies demonstrated significant nicotinic-DA interactions with regard to memory function. The current results suggest that in the DA-nicotinic relationship DA stimulation is not necessary for the memory improvement caused by nicotine.

Authors
Levin, ED
MLA Citation
Levin, ED. "Chronic haloperidol administration does not block acute nicotine-induced improvements in radial-arm maze performance in the rat." Pharmacol Biochem Behav 58.4 (December 1997): 899-902.
PMID
9408193
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
58
Issue
4
Publish Date
1997
Start Page
899
End Page
902

Persisting learning deficits in rats after exposure to Pfiesteria piscicida.

Pfiesteria piscicida and other toxic Pfiesteria-like dinoflagellates have been implicated as a cause of fish kills in North Carolina estuaries and elsewhere. Accidental laboratory exposure of humans to P. piscicida has been reported to cause a complex syndrome including cognitive impairment. The current project was conducted to experimentally assess the possibility of cognitive effects of P. piscicida exposure in rats. Samples of water from aquaria in which P. piscicida zoospores were killing fish were frozen, a procedure that has been found to induce encystment. Thawed samples were injected into albino Sprague-Dawley rats. A significant learning impairment was documented in rats administered samples of P. piscicida that were recently frozen. Prolonged storage of Pfiesteria samples diminished the effect. No effect was seen in the recall of a previously learned task, but when the rats were called upon to learn a new task, the Pfiesteria-treated animals showed a significant learning deficit. This effect persisted up to at least 10 weeks after a single injection of Pfiesteria. The Pfiesteria-induced learning deficit did not seem to be associated with any obvious debilitation or health impairment of the exposed rats. Deficits in habituation of arousal and rearing behavior were detected using a functional observational battery. No Pfiesteria-induced effects on blood count and white cell differential or in a standard pathological screening of brain, liver, lung, kidney, and spleen tissue were seen at 2 months after exposure. These studies document a persistent learning impairment in rats after exposure to the dinoflagellate P.piscicida in otherwise physically well-appearing rats. This effect may partially model the symptoms of cognitive impairments that humans have shown after Pfiesteria exposure.

Authors
Levin, ED; Schmechel, DE; Burkholder, JB; Deamer-Melia, NJ; Moser, VC; Harry, GJ
MLA Citation
Levin, ED, Schmechel, DE, Burkholder, JB, Deamer-Melia, NJ, Moser, VC, and Harry, GJ. "Persisting learning deficits in rats after exposure to Pfiesteria piscicida." Environ Health Perspect 105.12 (December 1997): 1320-1325.
PMID
9405328
Source
pubmed
Published In
Environmental health perspectives
Volume
105
Issue
12
Publish Date
1997
Start Page
1320
End Page
1325

Nicotinic system involvement in Alzheimer's and Parkinson's diseases. Implications for therapeutics.

Advances in our understanding of the structure, function and distribution of nicotinic acetylcholine receptors in the CNS have provided the impetus for new studies examining the role(s) that these receptors and associated processes may play in CNS functions. Further motivation has come from the realisation that such receptors must be involved in the maintenance of cigarette smoking, and from clues provided by studies of degenerative neurological diseases such as Alzheimer's disease and Parkinson's disease, in which the loss of nicotinic receptors has been described. Ongoing investigations of the molecular substructure of central nicotinic receptors and their pharmacology have begun to open up new possibilities for novel CNS therapeutics with nicotinic agents. Exploiting these possibilities will require understanding of the role(s) that these receptor systems play in human cognitive, behavioural, motor and sensory functioning. Clues from careful studies of human cognition are beginning to emerge and will provide direction for studies of potentially therapeutic novel nicotinic agents. Despite the promising results of acute studies, few long term studies with nicotine or nicotinic drugs have been performed in dementing disorders. Thus there is uncertainty as to whether long term nicotinic treatment will provide sustained cognitive benefit. It is even more uncertain whether such cognitive benefit will have a significant clinical impact on patients and their families. To maximise the potential benefit of long term treatment with nicotinic agonists (or other cholinergic drugs), we suggest that drug treatment should be combined with cognitive rehabilitation strategies. This will enable patients and/or their families to focus on the particular cognitive domains that may be improved.

Authors
Newhouse, PA; Potter, A; Levin, ED
MLA Citation
Newhouse, PA, Potter, A, and Levin, ED. "Nicotinic system involvement in Alzheimer's and Parkinson's diseases. Implications for therapeutics." Drugs Aging 11.3 (September 1997): 206-228. (Review)
PMID
9303280
Source
pubmed
Published In
Drugs & aging
Volume
11
Issue
3
Publish Date
1997
Start Page
206
End Page
228

Apoptosis and delayed neuronal damage after carbon monoxide poisoning in the rat.

Delayed neurological damage after CO hypoxia was studied in rats to determine whether programmed cell death (PCD), in addition to necrosis, is involved in neuronal death. In rats exposed to either air or CO (2500 ppm), microdialysis in brain cortex and hippocampus was performed to determine the extent of glutamate release and hydroxyl radical generation during the exposures. Groups of control and CO-exposed rats also were tested in a radial maze to assess the effects of the CO exposures on learning and memory. At 3, 7, and 21 days after CO exposure brains were perfusion-fixed and hematoxylin-eosin (H&E) was used to assess injury and to select regions for further examination. DNA fragmentation was sought by examining cryosections with the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) reaction. We found significant increases in glutamate release and .OH generation during and immediately after CO hypoxia. CO-exposed rats showed learning and memory deficits after exposure associated with heterogeneous cell loss in cortex, globus pallidus, and cerebellum. The frontal cortex was affected most seriously; the damage was slight at Day 3, increased at Day 7, and persistent at Day 21 after CO exposure. TUNEL staining was positive at all three time points, and TUNEL-labeled cells were distributed similarly to eosinophilic cells. The number of cells stained by TUNEL was less than by H&E and amounted to 2 to 5% of all cell nuclei in regions of injury. Ultrastructural features of both neuronal necrosis and apoptosis also were observed readily by electron microscopy. These findings indicate that both necrosis and apoptosis (PCD) contribute to CO poisoning-induced brain cell death.

Authors
Piantadosi, CA; Zhang, J; Levin, ED; Folz, RJ; Schmechel, DE
MLA Citation
Piantadosi, CA, Zhang, J, Levin, ED, Folz, RJ, and Schmechel, DE. "Apoptosis and delayed neuronal damage after carbon monoxide poisoning in the rat." Exp Neurol 147.1 (September 1997): 103-114.
PMID
9294407
Source
pubmed
Published In
Experimental Neurology
Volume
147
Issue
1
Publish Date
1997
Start Page
103
End Page
114
DOI
10.1006/exnr.1997.6584

Chronic nicotinic agonist and antagonist effects on T-maze alternation.

A variety of studies have found that nicotine improves working memory function. However, other studies have either not found improvements or have found nicotine-induced deficits. The demands of the particular memory test may be critical for the expression of the nicotine effects. In several studies, we have found that chronic nicotine administration improves working memory performance in the radial arm maze. Chronic mecamylamine coadministration reversed this effect. The current study was conducted to determine the effects of chronic nicotine and mecamylamine on choice accuracy in a T-maze spatial alternation task. The same dose and duration of nicotine administration that we have previously found to significantly improve choice accuracy in the radial-arm maze was not effective in altering T-maze spatial alternation. The critical difference in task demands may be the presence with T-maze alternation of proactive interference. During a session, a choice alternative repeatedly changes valence from correct to incorrect and back again. In contrast, with the radial-arm maze as run in our studies, in a session the valence of an arm only changes once from correct to incorrect. Previous work with nicotine effects on spatial alternation in an operant task found evidence that nicotine increased the negative effect of proactive interference on performance. In the current study, chronic mecamylamine caused a significant deficit in T-maze spatial alternation. This same dose did not produce a deficit in the radial-arm maze and, in fact, caused an improvement during the first week of administration.

Authors
Levin, ED; Christopher, NC; Briggs, SJ
MLA Citation
Levin, ED, Christopher, NC, and Briggs, SJ. "Chronic nicotinic agonist and antagonist effects on T-maze alternation." Physiol Behav 61.6 (June 1997): 863-866.
PMID
9177558
Source
pubmed
Published In
Physiology & Behavior
Volume
61
Issue
6
Publish Date
1997
Start Page
863
End Page
866

Acute nicotine interactions with nicotinic and muscarinic antagonists: working and reference memory effects in the 16-arm radial maze.

In the 8-arm radial maze and other tests, acute nicotine administration has been found to improve memory performance significantly, whereas acute administration of the nicotinic antagonist mecamylamine has been found to impair memory performance. However, questions remain concerning the behavioral and pharmacological nature of acute nicotine effects on memory. In the current studies, we examined acute nicotine effects on working and reference memory in a 16-arm radial maze. In the first study, nicotine caused a significant improvement in working memory but not in reference memory. The muscarinic antagonist scopolamine caused significant deficits in working memory but not in reference memory. Nicotine did not significantly attenuate the scopolamine-induced deficit. In the second study, with rats trained to near-perfect performance, a low dose of mecamylamine (1.25 mg/kg) caused a significant working memory impairment in the 16-arm maze. This deficit was significantly attenuated by concurrent acute administration of nicotine. These studies show that acute nicotine, like chronic nicotine, preferentially improves working compared with reference memory in the radial-arm maze. Mecamylamine can impair working memory performance in the 16-arm maze at low doses which are less likely to have effects at N-methyl-D-aspartate receptors. Nicotine can selectively reverse mecamylamine-induced deficits.

Authors
Levin, ED; Kaplan, S; Boardman, A
MLA Citation
Levin, ED, Kaplan, S, and Boardman, A. "Acute nicotine interactions with nicotinic and muscarinic antagonists: working and reference memory effects in the 16-arm radial maze." Behav Pharmacol 8.2-3 (June 1997): 236-242.
PMID
9833018
Source
pubmed
Published In
Behavioural Pharmacology
Volume
8
Issue
2-3
Publish Date
1997
Start Page
236
End Page
242

Is binding to nicotinic acetylcholine and dopamine receptors related to working memory in rats?

Nicotinic acetylcholine (ACh) and dopamine (DA) receptor activation has been found to be important for working memory. The regional distribution of these receptors in the brain has been well characterized. However, the relationship of the region-specific nicotinic ACh and DA binding density to memory performance has not been well assessed. In the current studies the relationship of receptor binding and memory function was examined. Receptor binding and memory performance were assessed in rats in three types of conditions: 1) chronic nicotine and mecamylamine vs. vehicle infusion; 2) lesions of the fimbria-fornix or medial basalocortical projection vs. sham lesions; and 3) 2-year-old aged rats vs. 3-month-old young adult rats. Nicotinic ACh receptors were labeled by [3H]N-methyl-carbamylcholine ([3H]MCC), D1 receptors by [3H]SCH 23390, and D2 receptors by [125I]iodosulpiride. Working memory was assessed using the radial-arm maze and T-maze delayed spatial alternation tasks. Chronic nicotine infusion substantially increased nicotinic receptor binding in a variety of brain areas and significantly improved working memory performance in the radial-arm maze. However, nicotinic receptor binding did not correlate well with memory performance. The nicotinic antagonist mecamylamine did not block nicotine-induced increased nicotinic binding, but it did block nicotine-induced memory improvement. Aged rats relative to young adults showed both a decrease in nicotinic binding and impaired memory performance. However, chronic effects of nicotine on nicotinic receptor binding and memory performance did not correlate in the aged rats. Nicotine also increased nicotinic receptor binding in the aged rats in brain areas except for the VTA, but did not improve memory performance. Lesions of the medial basalocortical projection or the fimbria-fornix did not cause significant changes in nicotinic binding in their target fields, but they did cause significant deficits in memory performance. Finally, there were no significant correlations of nicotinic binding in any brain region and memory performance. DA receptor binding was not altered by chronic nicotine or mecamylamine infusion, fimbria-fornix lesions, medial basalocortical lesions, or in aged rats. However, DA receptor binding did correlate with memory performance. There was a positive correlation of T-maze accuracy and D1 receptor binding in the frontal cortex and a negative correlation of T-maze accuracy and D1 receptor binding in the VTA and dentate gyrus. In contrast, a positive correlation was seen between radial-arm maze accuracy and D1 receptor binding in the VTA. Radial-arm maze accuracy was positively correlated with D2 receptor binding in the striatum and dentate gyrus. There are significant relationships between the extent of DA receptor binding and working memory, but relationship between nicotinic ACh receptor binding density and memory is weak.

Authors
Levin, ED; Torry, D; Christopher, NC; Yu, X; Einstein, G; Schwartz-Bloom, RD
MLA Citation
Levin, ED, Torry, D, Christopher, NC, Yu, X, Einstein, G, and Schwartz-Bloom, RD. "Is binding to nicotinic acetylcholine and dopamine receptors related to working memory in rats?." Brain Res Bull 43.3 (1997): 295-304.
PMID
9227840
Source
pubmed
Published In
Brain Research Bulletin
Volume
43
Issue
3
Publish Date
1997
Start Page
295
End Page
304

Prenatal nicotine effects on memory in rats: pharmacological and behavioral challenges.

Cigarette smoking during pregnancy has been shown in a variety of studies to be associated with cognitive deficits in the children. Nicotine administration to rats during gestation has been found to cause subtle cognitive effects in the offspring. Some individual differences in cognitive impairment may be related to prenatal nicotine effects on noradrenergic (NE) systems. In the current study, 10 Sprague-Dawley rat dams were infused with approximately 2 mg/kg/day of nicotine ditartrate via osmotic minipumps and 10 control dams were exposed to vehicle-containing minipumps from gestational day (GD) 4-20. Starting on postnatal day (PND) 50, the offspring were tested for T-maze rewarded spatial alternation with intertrial intervals of 0, 10, 20, or 40 s. There was a sex- and delay-dependent effect of prenatal nicotine exposure on T-maze alternation. Nicotine-exposed males showed a significant deficit at the 0 s delay. In radial-arm maze (RAM) acquisition training there were no significant nicotine effects. However, significant nicotine-related effects were seen with subsequent behavioral and pharmacological challenges in the RAM. Changing the RAM testing location to an identical maze in a different room elicited a significant choice accuracy deficit in the prenatal nicotine-exposed rats compared with controls. Acute nicotine challenge did not cause any differential effects in the prenatal nicotine and control groups. During the isoproterenol (beta-NE agonist) challenge phase there appeared a significant facilitation of choice accuracy and speeding of response in the prenatal nicotine exposure group which was not seen in the control group. The alpha-NE agonist phenylpropanolamine caused a significant deficit in control females but not in the females prenatally exposed to nicotine. No differential effects of the alpha-NE antagonist phenoxybenzamine were seen in the prenatal nicotine and control groups. Throughout RAM testing there was a significant sex effect with males having better choice accuracy than females. These results demonstrate that the persisting cognitive effects of prenatal exposure to 2 mg/kg/day cause subtle effects in cognitive performance which can be elicited with behavioral and pharmacological challenge. These results also support previous studies suggesting the involvement of NE systems in persisting effects of prenatal nicotine exposure.

Authors
Levin, ED; Wilkerson, A; Jones, JP; Christopher, NC; Briggs, SJ
MLA Citation
Levin, ED, Wilkerson, A, Jones, JP, Christopher, NC, and Briggs, SJ. "Prenatal nicotine effects on memory in rats: pharmacological and behavioral challenges." Brain Res Dev Brain Res 97.2 (December 23, 1996): 207-215.
PMID
8997505
Source
pubmed
Published In
Developmental Brain Research
Volume
97
Issue
2
Publish Date
1996
Start Page
207
End Page
215

Cognitive effects of neonatal hippocampal lesions in a rat model of schizophrenia.

Lesioning the ventral hippocampus of neonatal rats has been proposed as an experimental model of schizophrenia. This lesion causes a syndrome of hyperresponsivity to the stimulant effects of amphetamine, impaired grooming and disrupted social interactions, effects that emerge during adolescence, much like schizophrenia. Persisting cognitive effects of neonatal ventral hippocampal lesions were assessed in the current study, because the hippocampus is critically important for a variety of cognitive functions and cognitive impairment and because it is an important feature of schizophrenia. Spatial learning and working memory were assessed in the radial-arm maze, which is sensitive to the adverse effects of hippocampal lesions made in adults. Lesioned rats showed pronounced deficits in radial-arm maze choice accuracy that persisted throughout training. Deficits were seen during the prepubertal period as well as in adulthood. Even though the lesioned rats performed more poorly, they were significantly less sensitive to the amnestic effects of the nicotinic antagonist mecamylamine and the muscarinic antagonist scopolamine. No significant effects of nicotine or amphetamine were seen in either the lesioned or control groups. The long-lasting deficits in spatial learning and working memory resulting from neonatal ventral hippocampal lesions show that, unlike frontal cortical lesions during the same age, the effects of hippocampal lesions are not overcome during development. The resistance to the amnestic effects of nicotinic and muscarinic acetylcholine (ACh) antagonists suggests that the hippocampus is a critical site for the action of these drugs. Neonatal hippocampal lesions may provide a good model of the cognitive impairments of schizophrenia and may be useful to assess novel drug effects to counteract the cognitive deficits in schizophrenia.

Authors
Chambers, RA; Moore, J; McEvoy, JP; Levin, ED
MLA Citation
Chambers, RA, Moore, J, McEvoy, JP, and Levin, ED. "Cognitive effects of neonatal hippocampal lesions in a rat model of schizophrenia." Neuropsychopharmacology 15.6 (December 1996): 587-594.
PMID
8946433
Source
pubmed
Published In
Neuropsychopharmacology (Nature)
Volume
15
Issue
6
Publish Date
1996
Start Page
587
End Page
594
DOI
10.1016/S0893-133X(96)00132-7

Prenatal cocaine and/or nicotine exposure in rats: preliminary findings on long-term cognitive outcome and genital development at birth.

Prenatal cocaine or nicotine exposure is associated with a variety of teratogenic effects. The current study was conducted to determine their effects alone and in combination on cognitive function and sexual differentiation. Pregnant Long-Evans rats (N = 19) were exposed to either cocaine (15 mg/kg/dose b.i.d. SC on GD 8-20); nicotine (4 mg/kg/day continuous SC infusion on GD 4-20); both nicotine + cocaine; or vehicle only. Birth weight and anogenital distance (AGD) were measured in all pups at birth. Learning and memory were tested in the Morris water maze (MWM) during prepubertal and pubertal ages in five daily consecutive sessions and a sixth session 1 week later and in the radial-arm maze (RAM) during adulthood. In the RAM, a drug challenge of the beta-noradrenergic antagonist propranolol (10-20 mg/kg) was given after acquisition training. Maternal weight gain was reduced 13-42% and offspring birth weight was reduced by 7-12% in all three exposure groups compared to controls. Cocaine decreased the AGD of males (2.68 mm) compared to 2.88 mm in noncocaine-exposed male pups (p < 0.025). A sex-selective cocaine effect was also seen after adjustment of AGD measurements for body weight. With this measure cocaine-treated females showed significantly (p < 0.05) greater AGD than those not exposed to cocaine. In the MWM, there were two types of trials: cued reference memory trials and uncued spatial working memory trials. On cued reference memory trials significant cocaine-induced latency deficits were seen on only the first session. On spatial working memory trials cocaine-induced latency deficits were seen throughout daily training on sessions 1-5, but not the retention session 6, 1 week later. During RAM acquisition, there were no significant differences in choice accuracy between exposure groups. Following propranolol challenge, deficits in choice accuracy were demonstrated in rats prenatally exposed to cocaine or nicotine. These rats did not show any response to propranolol, whereas the controls slightly improved their choice accuracy. The results of this study indicated that prenatal cocaine exposure altered long-term cognitive function under basal conditions in the MWM and drug challenge in the RAM, birth weight, and genital development. Cocaine-induced cognitive deficits were predominately in working memory rather than reference memory or long-term retention. Prenatal nicotine exposure was only observed to alter birth weight and cognitive function in response to propranolol challenge in the RAM.

Authors
Cutler, AR; Wilkerson, AE; Gingras, JL; Levin, ED
MLA Citation
Cutler, AR, Wilkerson, AE, Gingras, JL, and Levin, ED. "Prenatal cocaine and/or nicotine exposure in rats: preliminary findings on long-term cognitive outcome and genital development at birth." Neurotoxicol Teratol 18.6 (November 1996): 635-643.
PMID
8947940
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
18
Issue
6
Publish Date
1996
Start Page
635
End Page
643

Nicotine-haloperidol interactions and cognitive performance in schizophrenics.

Nearly 90% of schizophrenics smoke cigarettes, considerably higher than the general population's rate of 25%. There is some indication that schizophrenics may smoke as a form of self-medication. Nicotine has a variety of pharmacologic effects that may both counteract some of the cognitive deficits of schizophrenia and counteract some of the adverse side effects of antipsychotic drugs. In the current study, we assessed the interactions of haloperidol and nicotine on cognitive performance of a group of schizophrenics. These patients were in a double-blind study, randomly assigning them to low, moderate, and high dose levels of haloperidol. The subjects, all smokers, came to the laboratory on four different mornings after overnight deprivation from cigarettes. In a double-blind fashion, they were administered placebo, low (7 mg/day), medium (14 mg/day), or high (21 mg/day) dose nicotine skin patches. Three hours after administration of the skin patch, the subjects were given a computerized cognitive test battery including: simple reaction time, complex reaction time (spatial rotation), delayed matching to sample, the Sternberg memory test, and the Conners continuous performance test (CPT). With the placebo nicotine patch, there was a haloperidol dose-related impairment in delayed matching to sample choice accuracy and an increase in response time on the complex reaction time task. Nicotine caused a dose-related reversal of the haloperidol-induced impairments in memory performance and complex reaction time. In the CPT, nicotine reduced the variability in response that is associated with attentional deficit. These results demonstrate the effects of nicotine in reversing some of the adverse side effects of haloperidol and improving cognitive performance in schizophrenia.

Authors
Levin, ED; Wilson, W; Rose, JE; McEvoy, J
MLA Citation
Levin, ED, Wilson, W, Rose, JE, and McEvoy, J. "Nicotine-haloperidol interactions and cognitive performance in schizophrenics." Neuropsychopharmacology 15.5 (November 1996): 429-436.
PMID
8914115
Source
pubmed
Published In
Neuropsychopharmacology (Nature)
Volume
15
Issue
5
Publish Date
1996
Start Page
429
End Page
436
DOI
10.1016/S0893-133X(96)00018-8

Chronic nicotine working and reference memory effects in the 16-arm radial maze: interactions with D1 agonist and antagonist drugs.

Chronic nicotine infusion has been found in a series of studies in our laboratory to significantly improve choice accuracy of rats in the eight-arm radial maze. The current study was designed to compare the effects of chronic nicotine infusion on working and reference memory in a 16-arm radial maze. Nicotine was administered to female Sprague-Dawley rats at approximately 5 mg/kg per day SC via osmotic minipumps. Controls received saline infusions. Chronic nicotine infusion significantly lowered the number of working memory errors compared to controls, whereas the number of reference memory errors was not significantly affected. The modest nicotine-induced reduction in working memory errors was seen as a main effect over the 4 weeks of infusion, but the clearest effect was seen in weeks 3-4 of nicotine administration. For the 2 weeks after withdrawal, the nicotine effect was no longer evident. Acute D1 challenges were given with the D1 agonist dihydrexidine (0, 0.25, 0.5 and 1 mg/kg) and the D1 antagonist SCH 23390 (0, 0.005, 0.015 and 0.05 micrograms/kg) during weeks 3-4 of chronic nicotine administration and weeks 1-2 after withdrawal from nicotine. Dihydrexidine caused a modest dose-related increase in reference memory errors but not working memory errors in the nicotine-treated, but not the control rats. The D1 antagonist SCH 23390 caused a modest though significant decrease in reference memory errors but not working memory errors in the control, but not the nicotine-treated rats. The behavioral specificity of chronic nicotine infusion was demonstrated with selective improvement in working memory function. Pharmacological interactions were seen with chronic nicotine treatment increasing responsivity to D1 agonist and decreasing responsivity to a D1 antagonist with regard to reference memory. The mechanisms of this interaction are still undiscovered.

Authors
Levin, ED; Kim, P; Meray, R
MLA Citation
Levin, ED, Kim, P, and Meray, R. "Chronic nicotine working and reference memory effects in the 16-arm radial maze: interactions with D1 agonist and antagonist drugs." Psychopharmacology (Berl) 127.1 (September 1996): 25-30.
PMID
8880940
Source
pubmed
Published In
Psychopharmacology
Volume
127
Issue
1
Publish Date
1996
Start Page
25
End Page
30

Hippocampal long-term potentiation and spatial learning in the rat: effects of GABAB receptor blockade.

This series of experiments assessed the role of GABAB receptors in the induction of long-term potentiation in the dentate gyrus in vivo, and spatial learning and memory in three different tasks. In urethane-anesthetized rats, the GABAB receptor antagonist CGP 46381 was injected intraperitoneally at a dose which effectively suppressed GABAB-mediated paired pulse disinhibition. Theta-burst stimulation reliably produced long-term potentiation in control rats. However, GABAB receptor blockade significantly suppressed the induction of long-term potentiation in the dentate gyrus. To compare the results of the long-term potentiation experiments with behavior, we assessed the performance of rats on several spatial learning and memory tasks in the presence of CGP 46381. We found that the working memory performance of highly trained rats on the eight-arm radial maze was unaffected by CGP 46381. There was also no effect of GABAB receptor blockade on learning in the eight-arm maze using a five-trial repeated acquisition paradigm. However, when we tested spatial learning in naive rats using a mildly stressful water maze task, we found that CGP 46381 substantially impaired both the latency to find the platform and the path-length travelled in the maze during acquisition. CGP 46381-treated rats took longer to learn the location of the escape platform and travelled a greater distance over the acquisition trials. These data demonstrate that GABAB receptor blockade results in a suppression of hippocampal long-term potentiation in vivo and impairs spatial learning in a task where stress may be a component of performance.

Authors
Brucato, FH; Levin, ED; Mott, DD; Lewis, DV; Wilson, WA; Swartzwelder, HS
MLA Citation
Brucato, FH, Levin, ED, Mott, DD, Lewis, DV, Wilson, WA, and Swartzwelder, HS. "Hippocampal long-term potentiation and spatial learning in the rat: effects of GABAB receptor blockade." Neuroscience 74.2 (September 1996): 331-339.
PMID
8865186
Source
pubmed
Published In
Neuroscience
Volume
74
Issue
2
Publish Date
1996
Start Page
331
End Page
339

Nicotinic, muscarinic and dopaminergic actions in the ventral hippocampus and the nucleus accumbens: effects on spatial working memory in rats.

Acetylcholine (ACh) systems have been widely shown to be important for memory. In particular, ACh hippocampal neurons are critical for memory formation, though ACh innervation of other areas such as the nucleus accumbens may also be important. There has also been increasing interest in ACh and dopaminergic (DA) interactions with regard to short-term spatial memory. In a series of studies, we have found that ACh and DA agonists and antagonists given systemically interact to influence memory. The critical neural loci of these interactions are not currently known. In the present study, we used local infusion techniques to examine the role of ACh and DA transmitter systems in the nucleus accumbens and the ventral hippocampus on radial-arm maze (RAM) working memory performance. Into the nucleus accumbens of rats, we infused the nicotinic ACh agonist nicotine, the nicotinic ACh antagonist mecamylamine, the DA agonist apomorphine, or the DA antagonist haloperidol. Into the ventral hippocampus, we infused nicotine, mecamylamine, the muscarinic ACh agonist pilocarpine, or the muscarinic ACh antagonist, scopolamine. The nicotinic ACh and DA interaction was tested by a hippocampal infusion of mecamylamine alone or together with the DA D2 agonist quinpirole given via subcutaneous injection. The results confirmed that both nicotinic and muscarinic ACh receptors in the ventral hippocampus play a significant role in spatial working memory. Blockade of either nicotinic or muscarinic ACh receptors caused significant impairments in RAM choice accuracy. However, infusion of either nicotinic or muscarinic agonists failed to improve choice accuracy. The interaction of DA D2 systems in different with hippocampal nicotinic blockade than with general nicotinic blockade. Systemic administration of quinpirole potentiated the amnestic effect of mecamylamine infused into the ventral hippocampus, whereas it was previously found to reverse the amnestic effect of systemically administered mecamylamine. In contrast to the significant effects of mecamylamine in the hippocampus, no effects were found after infusion into the nucleus accumbens. Nicotine also was not found to have a significant effect on memory after intra-accumbens infusion. Neither the DA agonist apomorphine nor the DA antagonist haloperidol had a significant effect on memory after infusion into the nucleus accumbens. This study provides support for the involvement of nicotinic and muscarinic receptors in the ventral hippocampus in memory function. Ventral hippocampal nicotinic systems have significant interactions with D2 systems, but these differ from their systemic interactions. In contrast, nicotinic ACh and DA systems in the nucleus accumbens were not found in the current study to be important for working memory performance in the RAM.

Authors
Kim, JS; Levin, ED
MLA Citation
Kim, JS, and Levin, ED. "Nicotinic, muscarinic and dopaminergic actions in the ventral hippocampus and the nucleus accumbens: effects on spatial working memory in rats." Brain Res 725.2 (July 1, 1996): 231-240.
PMID
8836529
Source
pubmed
Published In
Brain Research
Volume
725
Issue
2
Publish Date
1996
Start Page
231
End Page
240

Acute and chronic nicotine effects on working memory in aged rats.

Acute and chronic nicotine administration has been repeatedly been found in our laboratory to improve working memory performance of normal adult rats in the radial-arm maze. The current study was conducted to determine if acute or chronic nicotine administration would improve working memory performance in aged rats. Sixteen young adult (3-7 months) and 32 aged (24-28 months) male Sprague-Dawley rats were trained on an eight-arm radial maze. A significant age-related choice deficit was seen during the 21 sessions of training. After training, half of the rats in each age group were implanted with nicotine-containing osmotic minipumps and the other half implanted with vehicle-containing pumps. Consistent with previous work, the young adult rats given chronic nicotine (approximately 5 mg/kg per day as measured as nicotine base) showed a significant improvement in working memory performance. In contrast, the aged rats did not show a significant effect of this dose of chronic nicotine. After a 2 week withdrawal period the remaining rats underwent a series of acute drug challenges with nicotinic and muscarinic agonists and antagonists as well as the dopaminergic antagonist haloperidol. Mecamylamine and haloperidol impaired the memory performance of the young adult rats, whereas the aged rats showed no effect. In contrast, scopolamine impaired performance of both young adult and aged rats in a similar manner. Both pilocarpine and nicotine improved the memory performance of the aged rats, but did not improve the young adult rats, possibly due to a ceiling effect on performance. During the cholinergic agonist drug phase, the aged rats which had previously been given chronic nicotine infusions showed better performance than those which had not. The resistance of the aged rats to chronic nicotine-induced working memory improvements and acute mecamylamine-induced working memory deficits may have resulted from the decline in nicotinic receptors seen with aging. Chronic co-administration of the nicotinic antagonist mecamylamine in a previous study was found to abolish the chronic nicotine-induced working memory improvement. The aged rats were resistant to haloperidol-induced deficits which may have resulted from the decrease in dopaminergic receptors seen with aging. Interestingly, acute cholinergic agonists including nicotine did improve working memory performance in the aged rats and previous chronic nicotine infusion was beneficial during the period of acute cholinergic agonist challenge. This suggests that nicotinic treatment may be of use for treating age associated memory impairments but that special dosing regimens may be required.

Authors
Levin, ED; Torry, D
MLA Citation
Levin, ED, and Torry, D. "Acute and chronic nicotine effects on working memory in aged rats." Psychopharmacology (Berl) 123.1 (January 1996): 88-97.
PMID
8741959
Source
pubmed
Published In
Psychopharmacology
Volume
123
Issue
1
Publish Date
1996
Start Page
88
End Page
97

Nicotine effects on adults with attention-deficit/hyperactivity disorder.

Several lines of evidence suggest that nicotine may be useful in treating the symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD). The current study was an acute, placebo-controlled double-blind experiment to determine whether nicotine might be useful as an alternative treatment of adults with ADHD symptomatology. Six smokers and 11 nonsmokers who were outpatient referrals for ADHD were diagnosed by DSM-IV criteria. Measures of treatment effect included the Clinical Global Impressions (CGI) scale, Hopkins' symptom check list (SCL-90-R), the Profile of Mood States (POMS), Conners' computerized Continuous Performance Test (CPT), the Stroop test, and an interval-timing task. The smokers underwent overnight deprivation from smoking and were given a 21 mg/day nicotine skin patch for 4.5 h during a morning session. The nonsmokers were given a 7 mg/day nicotine skin patch for 4.5 h during a morning session. Active and placebo patches were given in a counter-balanced order approximately 1 week apart. Nicotine caused a significant overall nicotine-induced improvement on the CGI. This effect was significant when only the nonsmokers were considered, which indicated that it was not due merely to withdrawal relief. Nicotine caused significantly increased vigor as measured by the POMS test. Nicotine caused an overall significant reduction in reaction time (RT) on the CPT, as well as, with the smokers, a significant reduction in another index of inattention, variability in reaction time over trial blocks. Nicotine improved accuracy of time estimation and lowered variability of time-estimation response curves. Because improvements occurred among nonsmokers, the nicotine effect appears not to be merely a relief of withdrawal symptoms. It is concluded that nicotine deserves further clinical trials with ADHD.

Authors
Levin, ED; Conners, CK; Sparrow, E; Hinton, SC; Erhardt, D; Meck, WH; Rose, JE; March, J
MLA Citation
Levin, ED, Conners, CK, Sparrow, E, Hinton, SC, Erhardt, D, Meck, WH, Rose, JE, and March, J. "Nicotine effects on adults with attention-deficit/hyperactivity disorder." Psychopharmacology (Berl) 123.1 (January 1996): 55-63.
PMID
8741955
Source
pubmed
Published In
Psychopharmacology
Volume
123
Issue
1
Publish Date
1996
Start Page
55
End Page
63
DOI
10.1007/BF02246281

Nicotine and attention in adult attention deficit hyperactivity disorder (ADHD).

Nicotine, like the psychostimulants methylphenidate and dextroamphetamine, acts as an indirect dopamine agonist and improves attention and arousal. Adults and adolescents with attention deficit hyperactivity disorder (ADHD) smoke much more frequently than normal individuals or those with other psychiatric conditions, perhaps as a form of self-medication for ADHD symptoms. Nicotine might therefore have some value as a treatment for ADHD. The present study is an acute double-blind crossover administration of nicotine and placebo with smokers (n = 6) and nonsmokers (n = 11) diagnosed with adult ADHD. The drug was delivered via a transdermal patch at a dosage of 7 mg/day for nonsmokers and 21 mg/day for smokers. Results indicate significant clinician-rated global improvement, self-rated vigor and concentration, and improved performance on chronometric measures of attention and timing accuracy. Side effects were minimal. These acute results indicate the need for a longer clinical trial and a comparison with other stimulants in adult ADHD treatment.

Authors
Conners, CK; Levin, ED; Sparrow, E; Hinton, SC; Erhardt, D; Meck, WH; Rose, JE; March, J
MLA Citation
Conners, CK, Levin, ED, Sparrow, E, Hinton, SC, Erhardt, D, Meck, WH, Rose, JE, and March, J. "Nicotine and attention in adult attention deficit hyperactivity disorder (ADHD)." Psychopharmacol Bull 32.1 (1996): 67-73.
PMID
8927677
Source
pubmed
Published In
Psychopharmacology bulletin
Volume
32
Issue
1
Publish Date
1996
Start Page
67
End Page
73

Nicotinic agonist and antagonist effects on memory

Nicotine has been found by a variety of investigators to improve memory in rats, monkeys, and humans. Recent studies have helped to determine the behavioral and pharmacological nature of critical nicotine effects on memory function. Other nicotinic agonists, including ABT-418, GTS-21, or lobeline, can also significantly improve memory performance. Conversely, nicotinic antagonists, such as mecamylamine, can impair memory. Nicotine can reverse memory impairments caused by aging or by lesions to hippocampal connections. The observation that nicotine improves memory performance when it is administered by chronic infusion is potentially important for the development of treatments of cognitive impairment. Nicotinic agonists show promise for the development of novel treatments for cognitive disorders. Some characteristics of nicotine, nicotinic receptors, and the nature of the disorders to be treated, however, present challenges to the development of nicotinic-based treatments.

Authors
Levin, ED
MLA Citation
Levin, ED. "Nicotinic agonist and antagonist effects on memory." Drug Development Research 38.3-4 (1996): 188-195.
Source
scival
Published In
Drug Development Research
Volume
38
Issue
3-4
Publish Date
1996
Start Page
188
End Page
195
DOI
10.1002/(SICI)1098-2299(199607/08)38:3/4<188::AID-DDR7>3.0.CO;2-I

Chronic nicotine-induced improvement of spatial working memory and D2 dopamine effects in rats

Nicotine improves working memory function in a variety of different testing situations. In a series of studies, we have found that chronic nicotine infusion improves working memory performance of rats in the win-shift version of the radial-arm maze. In the current studies, we examined the interaction of chronic nicotine effects in the radial-arm maze with dopamine D2 agonist and antagonist drugs, since we have previously found significant interactions of acute nicotinic agonist and antagonist effects with D2 systems. Replicating our earlier results, significant nicotine-induced improvements in working memory performance were seen. Chronic co-infusion of raclopride, a D2 antagonist, or quinpirole, D2/D3 agonist, were not found to significantly interact with the choice accuracy improvement caused by nicotine. Acute challenge with a range of quinpirole doses also did not affect the facilitating effect of chronic nicotine. This stands in contrast to the significant interactions of D2 systems with acute nicotine effects. Acute and chronic nicotine administration have similar effects of facilitating memory performance in the radial-arm maze. However, these effects appear to have differential interactions with D2 systems.

Authors
Levin, ED; Christopher, NC; Briggs, SJ; Auman, JT
MLA Citation
Levin, ED, Christopher, NC, Briggs, SJ, and Auman, JT. "Chronic nicotine-induced improvement of spatial working memory and D2 dopamine effects in rats." Drug Development Research 39.1 (1996): 29-35.
Source
scival
Published In
Drug Development Research
Volume
39
Issue
1
Publish Date
1996
Start Page
29
End Page
35
DOI
10.1002/(SICI)1098-2299(19960901)39:1<29::AID-DDR4>3.0.CO;2-M

Epibatidine, a potent nicotinic agonist: Effects on learning and memory in the radial-arm maze

Epibatidine is a potent nicotinic agonist originally isolated from frog skin. Nicotine has been found in a variety of studies to improve working memory function in several different tests including the radial-arm maze (RAM). The current studies were conducted to determine if epibatidine would affect learning and memory in the radial-arm maze. Three studies were conducted. In the first study, rats were pretrained on the radial-arm maze and then given acute doses of epibatidine (0, 0.25, 0.5 and 1.0 μg/kg) in a repeated measures counter-balanced design. Compared to memory performance either before or after the drug study, performance during the drug study was significantly improved. This was true even with the intercurrent saline injections. This may have resulted from persisting effects of epibatidine administration. Because of this possibility of carryover effects the other studies both used between subjects designs. In the second study the rats were given 0, 0.5 or 1.0 μg/kg of epibatidine in a between subjects design throughout 24 sessions of RAM training. The rats given 0.5 μg/kg had a trend toward improved choice accuracy performance relative to control during the middle phase of learning. The higher dose had no apparent effect. To determine if the transience of the improvement caused by 0.5 μg/kg of epibatidine was due to the chronicity of the treatment or the phase of training a third study was conducted in which rats were pretrained for 12 sessions and then were given 0.5 μg/kg of epibatidine in a between subjects design for an additional 24 sessions of training. In this study when epibatidine was only given during the later phases of training no improvement was seen. In fact, a significant epibatidine deficit was seen during the final phase of training. These studies show that the potent nicotinic agonist epibatidine can significantly impair choice accuracy performance in the radial-arm maze. The expression of its effect depends critically on when during training it is given.

Authors
Levin, ED; Toll, K; Chang, G; Christopher, NC; Briggs, SJ; Fiedler, W
MLA Citation
Levin, ED, Toll, K, Chang, G, Christopher, NC, Briggs, SJ, and Fiedler, W. "Epibatidine, a potent nicotinic agonist: Effects on learning and memory in the radial-arm maze." Medicinal Chemistry Research 6.7-8 (1996): 543-554.
Source
scival
Published In
Medicinal Chemistry Research
Volume
6
Issue
7-8
Publish Date
1996
Start Page
543
End Page
554

Nicotine and neurobehavioral function

Authors
Levin, ED; Rose, JE; Lippelio, P; Robinson, J
MLA Citation
Levin, ED, Rose, JE, Lippelio, P, and Robinson, J. "Nicotine and neurobehavioral function." Drug Development Research 38.3-4 (1996): 135--.
Source
scival
Published In
Drug Development Research
Volume
38
Issue
3-4
Publish Date
1996
Start Page
135-
DOI
10.1002/(SICI)1098-2299(199607/08)38:3/4<135::AID-DDR1>3.0.CO;2-N

Pergolide interactions with nicotine and pilocarpine in rats on the radial-arm maze.

Antagonists of nicotinic and muscarinic acetylcholinergic (ACh) receptors have significant interactions with dopaminergic (DA) ligands with regard to radial-arm maze choice accuracy. The current studies examined the interactions of agonists of nicotinic and muscarinic ACh receptors with the DA agonist pergolide. Pergolide given in a range from 0.03-1.0 mg/kg had no detectable effect on radial-arm maze choice accuracy when given alone. With this dose range there was a linear increase in response latency. Pergolide had significant interactive effects with the nicotinic and muscarinic agonists nicotine and pilocarpine. Given together with nicotine, pergolide produced a significantly elevated linear increase in accuracy relative to when it was given alone. With pilocarpine, pergolide had an inverted U-shaped effect improving choice accuracy at low to moderate doses of 0.03 and 0.1 mg/kg. These results support previous findings of DA-ACh interactions with regard to radial-arm maze choice accuracy. Combined DA-ACh treatment may be a useful treatment of cognitive dysfunction.

Authors
Levin, ED
MLA Citation
Levin, ED. "Pergolide interactions with nicotine and pilocarpine in rats on the radial-arm maze." Pharmacol Biochem Behav 52.4 (December 1995): 837-840.
PMID
8587928
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
52
Issue
4
Publish Date
1995
Start Page
837
End Page
840

Smoking in Vietnam combat veterans with post-traumatic stress disorder.

The present study investigated smoking prevalence, smoking motives, demographic variables and psychological symptoms in 124 help-seeking, male Vietnam combat veterans with post-traumatic stress disorder (PTSD). A high percentage of these veterans smoked (60%). Vietnam veterans with PTSD who smoked were more likely than those who did not smoke to report higher levels of PTSD symptoms, depression and trait anxiety. Increased depression was associated with increased automatic smoking. Smokers reported a high frequency of smoking in response to military memories. Implications for smoking interventions, cessation, and relapse prevention efforts are discussed.

Authors
Beckham, JC; Roodman, AA; Shipley, RH; Hertzberg, MA; Cunha, GH; Kudler, HS; Levin, ED; Rose, JE; Fairbank, JA
MLA Citation
Beckham, JC, Roodman, AA, Shipley, RH, Hertzberg, MA, Cunha, GH, Kudler, HS, Levin, ED, Rose, JE, and Fairbank, JA. "Smoking in Vietnam combat veterans with post-traumatic stress disorder." J Trauma Stress 8.3 (July 1995): 461-472.
PMID
7582610
Source
pubmed
Published In
Journal of Traumatic Stress
Volume
8
Issue
3
Publish Date
1995
Start Page
461
End Page
472

Effects of nicotinic dimethylaminoethyl esters on working memory performance of rats in the radial-arm maze.

Nicotine has been found to improve memory performance in a variety of tests, including the radial-arm maze. This improvement, together with the consistent finding of a decline in cortical nicotinic receptor concentration in Alzheimer's patients, has fueled the search for novel nicotinic ligands with therapeutic potential. In the current studies, a series of nicotinic compounds was tested for effects on working memory performance in the radial-arm maze. One of the three compounds tested, DMAE II (dimethylaminoethanol cyclohexyl carboxylate fumurate), produced significant improvements in working memory performance. In the first experiment, this drug produced a biphasic dose-response curve with improved performance at the 20-mg/kg dose but not at 10 or 40 mg/kg. In a second round of DMAE II administration, the same rats showed a significant improvement with the 40-mg/kg dose. In the second experiment, a new set of rats also showed a biphasic dose-response to DMAE II. The 20-mg/kg dose caused a significant improvement whereas the 40-mg/kg dose did not. Interactions of DMAE II with nicotine and mecamylamine were also studied. Nicotine (0.2 mg/kg) by itself caused a significant improvement in working memory performance. No additive effects of DMAE II with nicotine were seen. In fact, some attenuation of response was seen with the combination. Choice accuracy data for mecamylamine could not be analyzed because of excessive sedation and nonresponding. These studies show that, like nicotine, the nicotinic ligand DMAE II causes an improvement in radial-arm mace choice accuracy. The lack of additivity with nicotine may have been to the partial agonist effects of DMAE II.

Authors
Levin, ED; Rose, JE; Abood, L
MLA Citation
Levin, ED, Rose, JE, and Abood, L. "Effects of nicotinic dimethylaminoethyl esters on working memory performance of rats in the radial-arm maze." Pharmacol Biochem Behav 51.2-3 (June 1995): 369-373.
PMID
7667355
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
51
Issue
2-3
Publish Date
1995
Start Page
369
End Page
373

Acute and chronic nicotinic interactions with dopamine systems and working memory performance.

Nicotine has been found to improve memory performance in a variety of tests in rats, monkeys, and humans. Interactions of nicotinic systems with dopamine (DA) systems may be important for this effect. We conducted a series of studies of nicotinic agonist and antagonist interactions with DA systems using rats in a win-shift working memory task in the radial-arm maze. The working memory deficit caused by the nicotinic antagonist mecamylamine was potentiated by the D1/D2 DA antagonist haloperidol and the specific D2 antagonist raclopride. In contrast, the mecamylamine-induced deficit was reversed by co-administration of the D2/D3 agonist quinpirole. Nicotine also has significant interactions with dopamine drugs with regard to working memory performance in the radial-arm maze. The DA agonist pergolide did not by itself improve radial-arm maze memory performance, but when given together with nicotine it produced an elevated dose-dependent increase in choice accuracy. The D1 agonist SKF 38393 significantly impaired radial-arm maze choice accuracy. Nicotine was effective in reversing this deficit. When given together with nicotine, the D2/D3 agonist quinpirole improved RAM choice accuracy relative to either drug alone. Acute local infusion of mecamylamine to the midbrain DA nuclei effectively impairs working memory function in the radial-arm maze. In contrast to acute nicotinic manipulations, considerably less evidence exists that the effects of chronic nicotine administration are influenced by DA systems. This may be an example of the different neural substrates that underlie the memory improvement caused by acute and chronic nicotine.

Authors
Levin, ED; Rose, JE
MLA Citation
Levin, ED, and Rose, JE. "Acute and chronic nicotinic interactions with dopamine systems and working memory performance." Ann N Y Acad Sci 757 (May 10, 1995): 245-252. (Review)
PMID
7611680
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
757
Publish Date
1995
Start Page
245
End Page
252

Combined administration of agonist-antagonist as a method of regulating receptor activation.

Authors
Rose, JE; Levin, ED; Behm, FM; Westman, EC; Stein, RM; Lane, JD; Ripka, GV
MLA Citation
Rose, JE, Levin, ED, Behm, FM, Westman, EC, Stein, RM, Lane, JD, and Ripka, GV. "Combined administration of agonist-antagonist as a method of regulating receptor activation." Ann N Y Acad Sci 757 (May 10, 1995): 218-221.
PMID
7611676
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
757
Publish Date
1995
Start Page
218
End Page
221

Haloperidol increases smoking in patients with schizophrenia.

Ten patients with schizophrenia participated in 120-min free-smoking sessions when actively psychotic and free of antipsychotic medications, and again after the initiation of haloperidol treatment. During these free-smoking sessions they had access to cigarettes ad libitum. Their expired air carbon monoxide (CO) and plasma nicotine and cotinine levels were measured at the end of the 120-min free-smoking sessions. These patients smoked more after starting haloperidol treatment, relative to their baseline rate of smoking when free of antipsychotic medications, as evidenced by significantly higher expired CO and plasma nicotine levels.

Authors
McEvoy, JP; Freudenreich, O; Levin, ED; Rose, JE
MLA Citation
McEvoy, JP, Freudenreich, O, Levin, ED, and Rose, JE. "Haloperidol increases smoking in patients with schizophrenia." Psychopharmacology (Berl) 119.1 (May 1995): 124-126.
PMID
7675943
Source
pubmed
Published In
Psychopharmacology
Volume
119
Issue
1
Publish Date
1995
Start Page
124
End Page
126

NICOTINE SKIN PATCH TREATMENT AND ADVERSE REACTIONS - SKIN IRRITATION, SKIN SENSITIZATION, AND NICOTINE AS A HAPTEN - REPLY

Authors
LEVIN, ED
MLA Citation
LEVIN, ED. "NICOTINE SKIN PATCH TREATMENT AND ADVERSE REACTIONS - SKIN IRRITATION, SKIN SENSITIZATION, AND NICOTINE AS A HAPTEN - REPLY." JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY 15.2 (April 1995): 146-146.
Source
wos-lite
Published In
Journal of Clinical Psychopharmacology
Volume
15
Issue
2
Publish Date
1995
Start Page
146
End Page
146
DOI
10.1097/00004714-199504000-00017

PRENATAL COCAINE AND NICOTINE EXPOSURE IN RATS - EFFECTS ON LONG-TERM COGNITIVE OUTCOME AND SEXUAL-DIFFERENTIATION

Authors
CUTLER, AR; WILKERSON, AE; GINGRAS, JL; LEVIN, ED
MLA Citation
CUTLER, AR, WILKERSON, AE, GINGRAS, JL, and LEVIN, ED. "PRENATAL COCAINE AND NICOTINE EXPOSURE IN RATS - EFFECTS ON LONG-TERM COGNITIVE OUTCOME AND SEXUAL-DIFFERENTIATION." PEDIATRIC RESEARCH 37.4 (April 1995): A14-A14.
Source
wos-lite
Published In
Pediatric Research
Volume
37
Issue
4
Publish Date
1995
Start Page
A14
End Page
A14

Triphenyl phosphite-induced impairment of spatial alternation learning.

Triphenyl phosphite (TPP) is a weak acetylcholinesterase inhibitor and a type II organophosphorus compound-induced delayed neurotoxic agent. The current study examined the cognitive effects of a single 250 mg/kg ip dose of TPP administered to either 3-mo- or 1-yr-old male Sprague-Dawley rats. Starting 4 d after TPP administration, the rats began training on a T-maze spatial alternation task for food reinforcement. Over five sessions of acquisition training, the TPP-treated rats showed significantly lower alternation scores than controls. There was no difference in spatial alternation performance in the first session, when both groups were performing at near-chance levels. In sessions 2-5, the controls improved dramatically to an average of 85.3 +/- 3.2% correct, while the TPP-treated rats did not significantly change, with 69.7 +/- 3.1 percent correct. During sessions 2 and 3 there was a significant TPP treatment-related deficit. This TPP-induced choice accuracy deficit was persistent in that it was seen well after the acute exposure. With continued training the TPP-exposed rats were able to learn the task as well as controls. There were no significant TPP effects on response latency. These data show that acute TPP administration has persistent effects of impairing T-maze learning that do not appear to result from effects on motor function.

Authors
Levin, ED; Christopher, NC; Abou-Donia, MB
MLA Citation
Levin, ED, Christopher, NC, and Abou-Donia, MB. "Triphenyl phosphite-induced impairment of spatial alternation learning." J Toxicol Environ Health 44.4 (April 1995): 461-467.
PMID
7723078
Source
pubmed
Published In
Journal of Toxicology and Environmental Health
Volume
44
Issue
4
Publish Date
1995
Start Page
461
End Page
467
DOI
10.1080/15287399509531974

Spatial working and reference memory in rats bred for autonomic sensitivity to cholinergic stimulation: acquisition, accuracy, speed, and effects of cholinergic drugs.

Rat lines were selected by breeding for sensitivity to signs of autonomic stimulation (hypotherma, loss of body weight, and reduced water intake) induced by the cholinesterase inhibitor diisopropyl fluorophosphate (DFP). These lines have since been maintained for 10 generations by continued selection for hypothermic responsiveness to the muscarinic agonist oxotremorine. The sensitive rats (Flinders Sensitive Line, FSL) differ from the resistant rats (Flinders Resistant Line, FRL) both neurochemically and behaviorally, particularly in aversively motivated test situations in which response speed is assessed. This study was conducted to determine whether the selected differences in cholinergic autonomic sensitivity would be expressed as differences in cognitive ability based on choice accuracy in appetitive tasks. The working and reference memory of rats of these two strains was thus assessed using operant delayed matching-to-position/visual discrimination (DMTP/VD) and the radial-arm maze. A Long-Evans (L-E) reference group was included in the DMTP/VD study. FSL rats responded more slowly than the other rats during acquisition of both tasks, but showed no differences in response accuracy either during acquisition or during asymptotic performance of either task. In addition, challenges with muscarinic and nicotinic antagonists and agonists [scopolamine (0.06-1.0 mg/kg), pilocarpine (1.0-4.0 mg/kg), mecamylamine (1.0-10.0 mg/kg), and nicotine (0.1-0.3 mg/kg)] demonstrated predicted differences in sensitivity among the lines only on performance measures such as response latency and trial completion. Counter to prediction, the sensitivity of the FRL rats to the ability of scopolamine to reduce matching accuracy was lower than those of the L-E and FSL rats. Thus selection based upon physiological endpoints related to cholinergic autonomic homeostasis did not produce analogous differences in cognitive function in rats.

Authors
Bushnell, PJ; Levin, ED; Overstreet, DH
MLA Citation
Bushnell, PJ, Levin, ED, and Overstreet, DH. "Spatial working and reference memory in rats bred for autonomic sensitivity to cholinergic stimulation: acquisition, accuracy, speed, and effects of cholinergic drugs." Neurobiol Learn Mem 63.2 (March 1995): 116-132.
PMID
7663885
Source
pubmed
Published In
Neurobiology of Learning and Memory
Volume
63
Issue
2
Publish Date
1995
Start Page
116
End Page
132
DOI
10.1006/nlme.1995.1012

Nicotine as a therapeutic drug.

Current evidence about the therapeutic potential of nicotine is strongest for ulcerative colitis. The role, if any, of nicotine therapy in Parkinson's or Alzheimer's diseases is not clear, but further research appears warranted. We need more information about the tolerability and safety of nicotine administration in such diseases. At present, any therapeutic trials of nicotine therapy should occur only as part of research protocols. Further nonjudgmental examination of the perceived effects of tobacco use may lead to other uses of nicotine. However, given the widespread morbidity and mortality directly attributable to tobacco use, no form of tobacco should be used to deliver nicotine. We encourage everyone who uses tobacco products to quit.

Authors
Westman, EC; Levin, ED; Rose, JE
MLA Citation
Westman, EC, Levin, ED, and Rose, JE. "Nicotine as a therapeutic drug." N C Med J 56.1 (January 1995): 48-51. (Review)
PMID
7862206
Source
pubmed
Published In
North Carolina Medical Journal
Volume
56
Issue
1
Publish Date
1995
Start Page
48
End Page
51

Nicotine effects on memory performance

Authors
LEVIN, ED; TORRY, D
MLA Citation
LEVIN, ED, and TORRY, D. "Nicotine effects on memory performance." 1995.
Source
wos-lite
Published In
EFFECTS OF NICOTINE ON BIOLOGICAL SYSTEMS II
Publish Date
1995
Start Page
329
End Page
335

Behavioral and neurochemical consequences of ibotenic acid lesion in the subthalamic nucleus of the common marmoset.

Five marmosets were unilaterally lesioned within the subthalamic nucleus (STN) by injection of 10 micrograms ibotenic acid. Seven marmosets served as saline injected controls. The lesioned marmosets showed an increased locomotor activity, occasional tongue protrusions, posture asymmetry, and abnormal movements of the contralateral legs and arms. The animals were sacrificed 21 days after the ibotenic acid injection and markers of gamma-aminobutyric acid (GABA), dopamine (DA), and acetylcholine were studied in a variety brain regions. There was a bilateral increase in the activity of glutamic acid decarboxylase (GAD) in the caudate, putamen, globus pallidus, superior colliculus, and the ventral anterior/ventral lateral (VA/VL) thalamus, whereas GABA concentrations were only increased ipsilaterally in the ventral posterior medial/centromedial/parafasciculus (VPM/CM/Pf) complex of the thalamus. Tyrosine hydroxylase (TH) activity was bilaterally increased in the medial segment of globus pallidus and nucleus accumbens. However, there were also changes restricted to the side contralateral to the lesion. TH activity and DA concentrations were increased contralateral to the lesion in the putamen. Choline acetyltransferase (CAT) activity was bilaterally increased in the medial segment of globus pallidus and hypothalamus. The ibotenic acid induced STN-lesion in the marmoset, thus, seemed to cause a widespread bilateral activation of neurons within the basal ganglia.

Authors
Andrén, PE; Levin, ED; Liminga, U; Gunne, L
MLA Citation
Andrén, PE, Levin, ED, Liminga, U, and Gunne, L. "Behavioral and neurochemical consequences of ibotenic acid lesion in the subthalamic nucleus of the common marmoset." Brain Res Bull 36.3 (1995): 301-307.
PMID
7697384
Source
pubmed
Published In
Brain Research Bulletin
Volume
36
Issue
3
Publish Date
1995
Start Page
301
End Page
307

Nicotine skin patch treatment and adverse reactions: Skin irritation, skin sensitization, and nicotine as a hapten [7]

Authors
Sudan, BJL; Levin, ED
MLA Citation
Sudan, BJL, and Levin, ED. "Nicotine skin patch treatment and adverse reactions: Skin irritation, skin sensitization, and nicotine as a hapten [7]." Journal of Clinical Psychopharmacology 15.2 (1995): 145-146.
PMID
7632289
Source
scival
Published In
Journal of Clinical Psychopharmacology
Volume
15
Issue
2
Publish Date
1995
Start Page
145
End Page
146
DOI
10.1097/00004714-199504000-00016

Clozapine decreases smoking in patients with chronic schizophrenia

Authors
McEvoy, J; Freudenreich, O; McGee, M; Vanderzwaag, C; Levin, E; Rose, J
MLA Citation
McEvoy, J, Freudenreich, O, McGee, M, Vanderzwaag, C, Levin, E, and Rose, J. "Clozapine decreases smoking in patients with chronic schizophrenia." Biological Psychiatry 37.8 (1995): 550-552.
PMID
7619979
Source
scival
Published In
Biological Psychiatry
Volume
37
Issue
8
Publish Date
1995
Start Page
550
End Page
552
DOI
10.1016/0006-3223(94)00365-A

[A transformylation reaction--transfer of an N-formyl residue to amino acids and peptides in nucleophilic groups--as a side reaction of peptide synthesis].

The formyl group transfer from N-formyl amino acids and their derivatives to other acceptors--amino acids esters and aniline, was studied. Formylamino acids with the free alpha-carboxyl group are more effective donors in transformylation than formyl peptides or esters of formylamino acids.

Authors
Kotlova, EK; Levin, ED; Iusupova, MP; Rozynov, BV; Stepanov, VM
MLA Citation
Kotlova, EK, Levin, ED, Iusupova, MP, Rozynov, BV, and Stepanov, VM. "[A transformylation reaction--transfer of an N-formyl residue to amino acids and peptides in nucleophilic groups--as a side reaction of peptide synthesis]." Bioorg Khim 20.11 (November 1994): 1186-1195.
PMID
7880178
Source
pubmed
Published In
Bioorganicheskaia khimiia
Volume
20
Issue
11
Publish Date
1994
Start Page
1186
End Page
1195

Working memory performance and cholinergic effects in the ventral tegmental area and substantia nigra.

The nicotinic antagonist mecamylamine has been found to impair working memory performance in the radial-arm maze (RAM) after s.c. or i.c.v. administration. Mecamylamine has important interactions with dopaminergic (DA) systems. Mecamylamine-induced memory deficits in the RAM are potentiated by the D2 antagonist raclopride and reversed by the D2 agonist quinpirole. The nicotinic agonist nicotine has been found to improve working memory performance in the RAM after s.c. or i.c.v. administration. Nicotine-induced memory improvement in the RAM is potentiated by the D2 agonist quinpirole. The midbrain DA nuclei, the substantia nigra (SN) and the ventral tegmental area (VTA) have relatively dense concentrations of nicotinic receptors which may be critical sites of action for mecamylamine and nicotine. In the current study, the effects of mecamylamine (1, 3.3 and 10 micrograms/side) infusions into the SN (n = 12) and VTA (n = 13) on working memory in the radial-arm maze were examined in adult female Sprague-Dawley rats. The 10-micrograms/side dose of mecamylamine significantly impaired radial-arm maze working memory performance when infused into either the SN or VTA. No significant effects of mecamylamine on response latency were seen. The nicotinic agonists cytisine (0.1, 0.33 and 1.0 microgram/side) and nicotine (0.3, 1.0 and 3.3 micrograms/side) were administered in a counterbalanced order. The high dose of cytisine (1 microgram/side) nearly caused a significant deficit in choice accuracy. Nicotine slightly depressed choice accuracy but not significantly in this study. The interaction of nicotine and mecamylamine was then studied. A dose of 1.0 microgram/side of nicotine caused a significant decrease in choice accuracy. Interestingly, this was significantly reversed by a 3.3-micrograms/side dose of mecamylamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Levin, ED; Briggs, SJ; Christopher, NC; Auman, JT
MLA Citation
Levin, ED, Briggs, SJ, Christopher, NC, and Auman, JT. "Working memory performance and cholinergic effects in the ventral tegmental area and substantia nigra." Brain Res 657.1-2 (September 19, 1994): 165-170.
PMID
7820615
Source
pubmed
Published In
Brain Research
Volume
657
Issue
1-2
Publish Date
1994
Start Page
165
End Page
170

Mecamylamine combined with nicotine skin patch facilitates smoking cessation beyond nicotine patch treatment alone.

OBJECTIVE: To evaluate concurrent administration of mecamylamine (nicotine antagonist) with nicotine skin patch treatment for smoking cessation. METHODS: This was a randomized, double-blind, placebo-controlled trial. Forty-eight healthy smokers who smoked at least one pack per day were studied at an outpatient smoking cessation research clinic. The subjects ranged in age from 20 to 40 years. Intervention with the nicotine skin patch (6 to 8 weeks) plus oral mecamylamine (2.5 to 5 mg twice a day for 5 weeks) was compared to nicotine patch plus placebo. Mecamylamine treatment began 2 weeks before smoking cessation. The primary outcome was continuous abstinence through 7 weeks after cessation (1 week after treatment), confirmed by expired air carbon monoxide measurements. Secondary measures included point abstinence at 7 weeks, continuous abstinence at 6- and 12-month follow-up, and self-reported withdrawal symptoms. RESULTS: The continuous abstinence rate at 7 weeks was three times higher in the mecamylamine condition: 50% versus 16.7%, p = 0.015. Point abstinence at 7 weeks was 58% for mecamylamine versus 29% for placebo, p = 0.044. At follow-up, continuous abstinence remained higher for mecamylamine: 37.5% versus 12.5% at 6 months (p = 0.046) and 37.5% versus 4.2% at 12 months (p = 0.004). Mecamylamine also significantly reduced craving for cigarettes, negative affect, and appetite. CONCLUSIONS: Agonist-antagonist therapy, consisting of the nicotine patch with oral mecamylamine, may substantially improve current smoking cessation treatment.

Authors
Rose, JE; Behm, FM; Westman, EC; Levin, ED; Stein, RM; Ripka, GV
MLA Citation
Rose, JE, Behm, FM, Westman, EC, Levin, ED, Stein, RM, and Ripka, GV. "Mecamylamine combined with nicotine skin patch facilitates smoking cessation beyond nicotine patch treatment alone." Clin Pharmacol Ther 56.1 (July 1994): 86-99.
PMID
8033499
Source
pubmed
Published In
Clinical Pharmacology & Therapeutics (Nature)
Volume
56
Issue
1
Publish Date
1994
Start Page
86
End Page
99

Nicotine skin patch treatment increases abstinence, decreases withdrawal symptoms, and attenuates rewarding effects of smoking.

A variety of studies have shown that nicotine skin patches are effective in promoting smoking cessation. This study replicated this effect, in addition, nicotine skin patches were found to decrease a variety of withdrawal effects, including craving for cigarettes, negative affect, hypoarousal, and increased appetite. This study also assessed the depressive symptoms shown by smokers before and after they quit smoking. Control subjects showed a significant increase in depressive symptoms after smoking cessation, whereas the subjects given the nicotine skin patch were not as affected. If the subjects slipped and smoked a cigarette during the time they were wearing the patch, they were asked to rate the effects of that cigarette. These "slip" cigarettes were rated significantly lower in satisfaction and good taste by subjects in the nicotine patch group than by controls. The nicotine skin patch may improve smoking cessation rates both by reducing nicotine withdrawal effects and by reducing the reward of slips back to smoking. This latter effect may prove to be effective in preventing slips from turning into relapses.

Authors
Levin, ED; Westman, EC; Stein, RM; Carnahan, E; Sanchez, M; Herman, S; Behm, FM; Rose, JE
MLA Citation
Levin, ED, Westman, EC, Stein, RM, Carnahan, E, Sanchez, M, Herman, S, Behm, FM, and Rose, JE. "Nicotine skin patch treatment increases abstinence, decreases withdrawal symptoms, and attenuates rewarding effects of smoking." J Clin Psychopharmacol 14.1 (February 1994): 41-49.
PMID
8151002
Source
pubmed
Published In
Journal of Clinical Psychopharmacology
Volume
14
Issue
1
Publish Date
1994
Start Page
41
End Page
49

CLOZAPINE DECREASES DRIVE TO SMOKE

Authors
MCEVOY, JP; ROSE, JE; LEVIN, ED; VANDERZWAAG, C; MCGEE, M
MLA Citation
MCEVOY, JP, ROSE, JE, LEVIN, ED, VANDERZWAAG, C, and MCGEE, M. "CLOZAPINE DECREASES DRIVE TO SMOKE." SCHIZOPHRENIA RESEARCH 11.2 (January 1994): 104-104.
Source
wos-lite
Published In
Schizophrenia Research
Volume
11
Issue
2
Publish Date
1994
Start Page
104
End Page
104

Promise of nicotinic-based therapeutic treatments

Nicotine has a wide variety of pharmacological effects. Some of these, such as improved attentiveness and memory, quickened reaction time, reduced appetite, and lessening of stress can be viewed as beneficial and may partially underlie tobacco use. They also suggest therapeutic uses of nicotine. Like any drug, nicotine has adverse effects as well, such as convulsant actions and cardiovascular effects. Also, like a variety of therapeutic drugs from caffeine to codeine, nicotine has the adverse potential to become habit forming or addictive. Many of the health damaging effects of tobacco use, such as cancer and lung disease, seem to result from compounds present in tar. Eliminating the more than 4,000 different compounds present in tar goes a long way in reducing adverse effects associated with nicotine intake. When developing nicotine for therapeutic use, it is critical to determine the mechanisms of its actions so that its beneficial effects can be maximized and its adverse effects can be minimized. This might be achieved with alternate routes of delivery of nicotine such as the skin patch or with novel nicotinic ligands currently under development.

Authors
Levin, ED; Rosecrans, JA
MLA Citation
Levin, ED, and Rosecrans, JA. "Promise of nicotinic-based therapeutic treatments." Drug Development Research 31.1 (1994): 1-2.
Source
scival
Published In
Drug Development Research
Volume
31
Issue
1
Publish Date
1994
Start Page
1
End Page
2

Nicotine interactions with dopamine agonists: Effects on working memory function

Nicotine has been found to improve memory performance in a variety of tests including the radial-arm maze. Nicotine may have effects mediated by promoting the release of dopamine. The present study was conducted to determine the interactions of nicotine with D1 and D2 agonists. Rats were acutely administered nicotine, the D1 agonist SKF 38393, and D2/D3 agonist quinpirole, and nicotine together with each of these agonists. Nicotine significantly improved choice accuracy in the radial-arm maze. The D1 agonist SKF 38393 significantly impaired choice accuracy. Nicotine was effective in reversing this effect. The D2/D3 agonist quinpirole showed a trend toward potentiating the improvement in choice accuracy caused by 0.2 mg/kg (0.43 μmol/kg) of nicotine. These data show that, as with the nicotinic antagonist mecamylamine, there are significant interactions of dopamine systems with nicotine effects.

Authors
Levin, ED; Eisner, B
MLA Citation
Levin, ED, and Eisner, B. "Nicotine interactions with dopamine agonists: Effects on working memory function." Drug Development Research 31.1 (1994): 32-37.
Source
scival
Published In
Drug Development Research
Volume
31
Issue
1
Publish Date
1994
Start Page
32
End Page
37

Combined Effects of Nicotine and Mecamylamine in Attenuating Smoking Satisfaction

Separate and combined effects of nicotine and the nicotinic antagonist mecamylamine were studied. Twelve smokers rated test cigarettes after administration of mecamylamine versus placebo capsules and nicotine versus nonnicotine preload. Smoking withdrawal symptoms, task performance, and cardiovascular activity were also measured. Mecamylamine attenuated smoking satisfaction, liking, and airway sensations. The nicotine preload similarly reduced the enjoyable aspects of subsequent test cigarettes, and this action of the preload was not prevented by mecamylamine. In contrast, mecamylamine blocked nicotine-related increases in heart rate and systolic blood pressure. Conversely, nicotine counteracted mecamylamine's effects on tapping speed and orthostatic blood pressure response. Although each drug offset potential side effects of the other, they acted in unison to attenuate smoking satisfaction and should be evaluated in combination for smoking cessation.

Authors
Rose, JE; Behm, FM; Westman, EC; Levin, ED; Stein, RM; Lane, JD; Ripka, GV
MLA Citation
Rose, JE, Behm, FM, Westman, EC, Levin, ED, Stein, RM, Lane, JD, and Ripka, GV. "Combined Effects of Nicotine and Mecamylamine in Attenuating Smoking Satisfaction." Experimental and Clinical Psychopharmacology 2.4 (1994): 328-344.
Source
scival
Published In
Experimental and Clinical Psychopharmacology
Volume
2
Issue
4
Publish Date
1994
Start Page
328
End Page
344

Intracerebroventricular nicotine and mecamylamine alter radial-arm maze performance in rats

In rats, the effects of an intracerebroventricular (ICV) nicotinic agonist nicotine (NIC), the nicotinic antagonist mecamylamine (MEC), and combinations of NIC + MEC were assessed in a radial-arm maze (RAM). In experiment 1, exploratory behavior was assessed in untrained rats (N = 13). The rats received 4 μg, 8.65 nmol NIC (NIC 4), 200 μg, 0.98 μmol MEC (MEC), and saline (SAL) ICV infusions. NIC 4 caused a significant increase in choice distribution compared to SAL (P < 0.025). In experiment 2, rats (N = 10) were trained to perform a working memory task for food reinforcement in the RAM. ICV doses of SAL, NIC 4, NIC 8, MEC, MECNIC 4, and MECNIC 8 were administered after completion of the training period. MEC caused a significant deficit in choice accuracy when compared to SAL (P < 0.025). This deficit was reversed when NIC 8 was coadministered with MEC (P < 0.05). There were no significant effects on choice latency for either study. The effects of ICV NIC and MEC on RAM performance are generally similar to their systemic effects in that NIC improves and MEC impairs choice accuracy. The reversal of the MEC-induced choice deficit by ICV NIC administration has not been reported with systemic administration. ICV MEC induces a choice accuracy deficit without increasing choice latency. This has not been seen with systemic MEC administration. The current result implies that the MEC-induced choice accuracy deficit did not result from MEC-induced sedation. The data indicate that previously reported changes in choice accuracy from peripherally administered NIC and MEC result from their central effects.

Authors
Brucato, FH; Levin, ED; Rose, JE; Swartzwelder, HS
MLA Citation
Brucato, FH, Levin, ED, Rose, JE, and Swartzwelder, HS. "Intracerebroventricular nicotine and mecamylamine alter radial-arm maze performance in rats." Drug Development Research 31.1 (1994): 18-23.
Source
scival
Published In
Drug Development Research
Volume
31
Issue
1
Publish Date
1994
Start Page
18
End Page
23

Saliva nicotine as an index of plasma levels in nicotine skin patch users.

This study examined whether salivary nicotine concentrations would provide a useful index of plasma concentrations in studies of the effects of transdermal nicotine administration. Twenty-four subject smokers abstained from smoking for 12 h prior to admission to a clinical research unit ward and for 36 h while remaining confined to the ward. Three doses of nicotine skin patches were applied to different groups of subjects, and blood and saliva samples were collected at several time points. Saliva flow was stimulated by three different methods: (a) sucking on a lemon candy, (b) dissolving a sugar cube in the mouth, and (c) chewing on parafilm. Nicotine and cotinine concentrations were measured in both saliva and blood using gas chromatography. There was a high correlation between blood and saliva values of nicotine (r = 0.82). Overall, saliva nicotine concentrations were approximately 8.1 times higher than those of plasma. Saliva and blood cotinine concentrations were also highly correlated (r = 0.94), replicating results of previous studies. Results suggest that saliva nicotine may be a useful marker of nicotine intake during nicotine skin patch treatment. Saliva collection may be advantageous under conditions in which blood collection is impractical and may provide greater sensitivity because of the high concentration of nicotine in saliva relative to that in blood.

Authors
Rose, JE; Levin, ED; Benowitz, N
MLA Citation
Rose, JE, Levin, ED, and Benowitz, N. "Saliva nicotine as an index of plasma levels in nicotine skin patch users." Ther Drug Monit 15.5 (October 1993): 431-435.
PMID
8249050
Source
pubmed
Published In
Therapeutic Drug Monitoring
Volume
15
Issue
5
Publish Date
1993
Start Page
431
End Page
435

Clinical trials using ascorbic acid aerosol to aid smoking cessation.

Sensory aspects of cigarette smoke are important for providing smoking satisfaction. In previous studies, we have found that substitution of the sensory cues of smoking with a citric acid aerosol significantly reduces craving for cigarettes and enhances smoking reduction and cessation with people trying to quit smoking cigarettes. In the current study, we conducted two clinical smoking cessation trials using an ascorbic acid aerosol as a sensory substitute. The cigarette substitute consisted of a cigarette-sized tube which delivered a fine aerosol of ascorbic acid (approx. 1 mg/puff, up to a maximum of 300 mg/day). Study 1 examined the overall effectiveness of the ascorbic acid smoking substitute device. One group of subjects which used the device and received clinical counseling was compared with another group which received only clinical counseling. The group using the device showed significantly greater abstinence rates at 3 weeks post-cessation. After the subjects stopped using the device, no difference in abstinence was detected. Study 2 was conducted to focus specifically on the role of tracheobronchial sensations in relieving craving for cigarettes. Two closely matched ascorbic acid delivery systems were compared. One device delivered fine particles of ascorbic acid that were targeted to reach the trachea, while the other delivered coarser particles of ascorbic acid that were not expected to reach the trachea or lower airways. An initial enhancement in smoking reduction was found for subjects using the fine particle device relative to those using the coarse particle device. However, by the end of treatment (5 weeks) both groups showed similar degrees of smoking reduction. For those who were abstinent from smoking at the end of treatment, craving for cigarettes and negative mood were both significantly lower for those using the fine particle device. Also, hunger for food was significantly lower in the fine particle device group. These results suggest that ascorbic acid delivered from a cigarette substitute may be effective in reducing smoking and promoting smoking abstinence.

Authors
Levin, ED; Behm, F; Carnahan, E; LeClair, R; Shipley, R; Rose, JE
MLA Citation
Levin, ED, Behm, F, Carnahan, E, LeClair, R, Shipley, R, and Rose, JE. "Clinical trials using ascorbic acid aerosol to aid smoking cessation." Drug Alcohol Depend 33.3 (October 1993): 211-223.
PMID
8261886
Source
pubmed
Published In
Drug and Alcohol Dependence
Volume
33
Issue
3
Publish Date
1993
Start Page
211
End Page
223

Chronic nicotine reverses working memory deficits caused by lesions of the fimbria or medial basalocortical projection.

Nicotine has been found in a variety of studies to improve performance in memory tasks. This study was conducted to determine if chronic nicotine administration is useful in counteracting the working memory deficits seen after lesions of the fimbria or the medial basalocortical projection. Rats were trained to asymptotic performance on a working memory version of the radial-arm maze. Then, they were given knife cut lesions of the fimbria or the medial basalocortical projection or underwent sham surgeries. At the time of surgery, rats in each treatment group were implanted with either nicotine-containing or placebo glass and Silastic pellets. Rats with fimbria or basalocortical lesions showed a significant decline in working memory performance. Chronic nicotine significantly improved choice accuracy in both lesioned and unlesioned rats. Nicotine treatment restored performance of the lesioned rats to control levels. These data show that in addition to improving memory performance in normal rats, nicotine can counteract lesion-induced memory impairments. Nicotine also may be useful for treatment of disease-related memory impairments such as seen in Alzheimer's disease.

Authors
Levin, ED; Christopher, NC; Briggs, SJ; Rose, JE
MLA Citation
Levin, ED, Christopher, NC, Briggs, SJ, and Rose, JE. "Chronic nicotine reverses working memory deficits caused by lesions of the fimbria or medial basalocortical projection." Brain Res Cogn Brain Res 1.3 (October 1993): 137-143.
PMID
8257869
Source
pubmed
Published In
Cognitive Brain Research
Volume
1
Issue
3
Publish Date
1993
Start Page
137
End Page
143

The nicotine patch in smoking cessation. A randomized trial with telephone counseling.

BACKGROUND: This study was conducted to determine the efficacy of the nicotine patch in smoking cessation when combined with self-help materials, three brief visits, and telephone counseling. METHODS: One hundred fifty-nine healthy volunteers who smoked at least one pack of cigarettes per day and desired to quit smoking were enrolled in a double-blind trial with 6-week treatment and 6-month follow-up periods. After review of self-help materials, subjects were randomly assigned to regimens of nicotine or placebo patches. Subjects wore two patches per day for 4 weeks (25 mg of nicotine per 24 hours), then one patch per day for 2 weeks. Return visits were at the ends of weeks 4 and 6. Telephone counseling was given during weeks 1, 2, 3, and 5. Abstinence at 6 weeks was defined as zero cigarettes smoked for the previous 28 days, verified by exhaled carbon monoxide less than 8 ppm at 4 weeks and 6 weeks. Abstinence at 3 and 6 months was defined as self-report of zero cigarettes since the previous contact, verified by carbon monoxide value at 6 months. RESULTS: Abstinence rates at 6 weeks, 3 months, and 6 months were 29.5%, 21.8%, and 20.5% in the active group, and 8.8%, 3.8%, and 2.5% in the placebo group (P < or = .001 for each comparison), respectively. Skin irritation was the main side effect, causing 1.3% to drop out. CONCLUSION: The nicotine patch is efficacious in smoking cessation over a 6-month period, when combined with only self-help materials, three brief visits, and telephone counseling.

Authors
Westman, EC; Levin, ED; Rose, JE
MLA Citation
Westman, EC, Levin, ED, and Rose, JE. "The nicotine patch in smoking cessation. A randomized trial with telephone counseling." Arch Intern Med 153.16 (August 23, 1993): 1917-1923.
PMID
8250653
Source
pubmed
Published In
Archives of internal medicine
Volume
153
Issue
16
Publish Date
1993
Start Page
1917
End Page
1923

Effects of dopaminergic drugs on working and reference memory in rats.

Changes in dopaminergic function have been associated with alterations in motor and cognitive function in man and in animals. This study was designed to assess the effects of dopaminergic drugs on these aspects of conditioned behavior in animals. Male Long-Evans rats were trained to perform an appetitive operant task that allowed daily quantification of working memory (accuracy of spatial delayed nonmatching-to-position), reference memory (accuracy of visual discrimination) and motor function [choice lever-press latency and nosepoke interresponse time (IRT) during delay]. The indirect dopamine agonist d-amphetamine (0.3-1.0 mg/kg) reduced nonmatching accuracy without significantly affecting discrimination accuracy, response latency, or nosepoke IRT. The D2/D3 agonist quinpirole (0.01-0.056 mg/kg) also decreased nonmatching accuracy without changing discrimination accuracy, but increased choice response latency and nosepoke IRT as well. The D1 agonist SKF 38393 (1.0-3.0 mg/kg) and the D1 antagonist SCH 23390 (0.01-0.03 mg/kg) only affected nosepoke IRT, at doses below those causing response failure. The D2 antagonist raclopride (0.056-0.177 mg/kg) exerted no significant effects at doses that did not suppress responding completely. The selective reduction of nonmatching accuracy by d-amphetamine and quinpirole indicates a mnemonic impairment specific to working memory (relative to reference memory). These results suggest further 1) that stimulation of D2/D3, but not D1, receptors may account for the d-amphetamine-induced deficit in working memory; 2) that stimulation of D2/D3 receptors alone by quinpirole may also impair spatial working memory, but only in conjunction with motor slowing; and 3) that antagonism of either receptor type (by SCH 23390 or raclopride) does not significantly affect memory at doses causing motor slowing and response failure.

Authors
Bushnell, PJ; Levin, ED
MLA Citation
Bushnell, PJ, and Levin, ED. "Effects of dopaminergic drugs on working and reference memory in rats." Pharmacol Biochem Behav 45.4 (August 1993): 765-776.
PMID
8105486
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
45
Issue
4
Publish Date
1993
Start Page
765
End Page
776

Prenatal nicotine exposure and cognitive performance in rats.

In humans and animal models there is evidence that prenatal nicotine exposure causes lasting deficits in cognitive performance. The current study examined the cognitive effects of prenatal exposure of rats to 2 mg/kg/day of nicotine. This dose did not cause significant deficits in maternal weight gain, offspring litter size, or pup weight. The control offspring showed the normal ontogeny of spontaneous alternation from near chance (50%) performance to 80%-85% alternation. In contrast, the nicotine-exposed rats had the opposite progression with abnormally high alternation on days 22-30 and abnormally low alternation on days 35-52. Acquisition of choice accuracy performance on the radial-arm maze (RAM) was not altered in a major way by nicotine exposure. Minor nicotine-induced changes in choice accuracy were seen during the initial trials of acquisition. The nicotine exposed female offspring had a significantly longer response duration. Prenatal nicotine exposure did significantly alter the effects of subsequent drug challenges on choice accuracy performance. The nicotine-exposed male offspring were significantly more responsive to the amnestic effects of the nicotinic antagonist mecamylamine. In a subsequent challenge, the effects of the beta-adrenergic antagonist propranolol were examined. A significant dose-related impairment in choice accuracy was seen in the control rats. In contrast, the nicotine-exposed rats did not show any significant response to propranolol. This decreased responsiveness to adrenergic challenge parallels the reduction in adrenergic response to nicotine challenge we previously found in littermates to the rats of the current study. Prenatal nicotine exposure causes subtle alterations in cognitive performance that can be magnified by challenges of nicotinic and adrenergic systems.

Authors
Levin, ED; Briggs, SJ; Christopher, NC; Rose, JE
MLA Citation
Levin, ED, Briggs, SJ, Christopher, NC, and Rose, JE. "Prenatal nicotine exposure and cognitive performance in rats." Neurotoxicol Teratol 15.4 (July 1993): 251-260.
PMID
8413079
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
15
Issue
4
Publish Date
1993
Start Page
251
End Page
260

Development of treatments for toxicant-induced cognitive deficits.

A wide variety of toxicants have been found to impair cognitive function. Some such as lead, organophosphate pesticides, and polychlorinated biphenyls are quite widespread in the environment. Others such as alcohol, nicotine, and cocaine are widely used drugs of abuse. Many people are chronically exposed to these toxicants. Lasting cognitive deficits can result, especially after developmental exposure. Considerable research has been directed at developing pharmacological agents to treat the cognitive dysfunction associated with Alzheimer's Disease, Unfortunately, other types of cognitive dysfunction, such as toxicant-induced cognitive deficits, have not received the same degree of attention, despite the fact that they are quite widespread and may be more amenable to development of useful therapeutic treatments. Animal models can be particularly useful because the agents causing these deficits are known. In addition, for a variety of neurotoxic compounds, information concerning the nature of the cognitive effect and mechanism of toxic action can help in development of treatments. Prevention of toxic exposure is ideal. Removal from the source of pollution after exposure can help, but for those who already carry the burden of persistent deficits, development of efficacious therapeutic treatments is a necessity.

Authors
Levin, ED
MLA Citation
Levin, ED. "Development of treatments for toxicant-induced cognitive deficits." Neurotoxicol Teratol 15.3 (May 1993): 203-206. (Review)
PMID
8336681
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
15
Issue
3
Publish Date
1993
Start Page
203
End Page
206

Chronic nicotinic stimulation and blockade effects on working memory.

Acute and chronic nicotine treatment has been found to improve learning and memory function in a variety of tasks. In several studies we have found that chronic nicotine infusion improves working memory performance. Replicating these results, the current study showed that chronic nicotine treatment (12mg/kg/day) significantly improved working memory performance in the radial-arm maze. The nicotine effect did not diminish during the 2 weeks following withdrawal. The nicotine-induced improvement was eliminated when the nicotinic antagonist mecamylamine (3mg/kg/day) was given concurrently, suggesting that the nicotine effect was mediated via actions on the nicotinic receptor. Surprisingly, when this chronic dose of mecamylamine was given alone, it caused a transient improvement in choice accuracy during the first week of administration. This improvement subsequently became attenuated and was not evident at all by the third and fourth weeks of administration.

Authors
Levin, ED; Briggs, SJ; Christopher, NC; Rose, JE
MLA Citation
Levin, ED, Briggs, SJ, Christopher, NC, and Rose, JE. "Chronic nicotinic stimulation and blockade effects on working memory." Behav Pharmacol 4.2 (April 1993): 179-182.
PMID
11224184
Source
pubmed
Published In
Behavioural Pharmacology
Volume
4
Issue
2
Publish Date
1993
Start Page
179
End Page
182

Role of nicotine dose and sensory cues in the regulation of smoke intake.

We investigated the role of nicotine dose and sensory cues in the regulation of ad lib smoke intake. The smoking behavior of 12 adult male smokers was assessed in three conditions, presenting either high-nicotine cigarette smoke (high nicotine, high sensory), diluted cigarette smoke (low nicotine, low sensory), or an aerosol containing cigarette smoke constituents suspended in solution, which was low in nicotine, yet high in sensory impact. Subjects showed marked compensatory increases in smoking with the dilute smoke conditions, whereas they puffed and inhaled the aerosol to a similar extent as the high-nicotine cigarette. Thus, subjects regulated their smoking behavior to equate sensory intensity rather than nicotine intake. Moreover, the aerosol and high-nicotine cigarette conditions lowered craving to a greater degree than the dilute smoke condition. Other mood indices, such as arousal and negative affect, were more effectively relieved by the high-nicotine dose condition. These results highlight the importance of sensory cues in the regulation of smoke intake and modulation of craving and suggest the clinical application of techniques for providing relief of cigarette craving during smoking cessation.

Authors
Rose, JE; Behm, FM; Levin, ED
MLA Citation
Rose, JE, Behm, FM, and Levin, ED. "Role of nicotine dose and sensory cues in the regulation of smoke intake." Pharmacol Biochem Behav 44.4 (April 1993): 891-900.
PMID
8469698
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
44
Issue
4
Publish Date
1993
Start Page
891
End Page
900

SMOKING WHILE WEARING THE NICOTINE PATCH - IS SMOKING STILL SATISFYING

Authors
WESTMAN, EC; LEVIN, ED; ROSE, JE
MLA Citation
WESTMAN, EC, LEVIN, ED, and ROSE, JE. "SMOKING WHILE WEARING THE NICOTINE PATCH - IS SMOKING STILL SATISFYING." CLINICAL RESEARCH 41.2 (April 1993): A573-A573.
Source
wos-lite
Published In
Clinical Research
Volume
41
Issue
2
Publish Date
1993
Start Page
A573
End Page
A573

PREDICTING SUCCESS OF THE NICOTINE PATCH IN SMOKING CESSATION USING BASE-LINE CLINICAL INFORMATION

Authors
WESTMAN, EC; SIMEL, DL; LEVIN, ED; ROSE, JE
MLA Citation
WESTMAN, EC, SIMEL, DL, LEVIN, ED, and ROSE, JE. "PREDICTING SUCCESS OF THE NICOTINE PATCH IN SMOKING CESSATION USING BASE-LINE CLINICAL INFORMATION." CLINICAL RESEARCH 41.2 (April 1993): A573-A573.
Source
wos-lite
Published In
Clinical Research
Volume
41
Issue
2
Publish Date
1993
Start Page
A573
End Page
A573

Clinical evaluation of a citric acid inhaler for smoking cessation.

In this study, we evaluated the efficacy of a hand-held inhaler as an adjunct to a smoking cessation behavioral program. The inhaler delivered a citric acid aerosol with tobacco smoke flavor. Seventy-four smokers were recruited for a 3-week smoking cessation trial. During the first 12 days of the cessation period, smokers used the citric acid aerosol inhaler instead of a cigarette whenever the urge to smoke occurred. The citric acid inhaler significantly reduced CO levels and enhanced rates of smoking abstinence for those with higher than average (34.2 ppm) baseline end-expired carbon monoxide (CO) levels. Craving for cigarettes and negative affect were also alleviated by the citric acid aerosol. These results suggest that the citric acid aerosol may promote successful smoking reduction or cessation in a subgroup of smokers and relieves withdrawal symptoms such as craving for cigarettes, a symptom difficult to treat with currently available nicotine replacement techniques.

Authors
Behm, FM; Schur, C; Levin, ED; Tashkin, DP; Rose, JE
MLA Citation
Behm, FM, Schur, C, Levin, ED, Tashkin, DP, and Rose, JE. "Clinical evaluation of a citric acid inhaler for smoking cessation." Drug Alcohol Depend 31.2 (January 1993): 131-138.
PMID
8436059
Source
pubmed
Published In
Drug and Alcohol Dependence
Volume
31
Issue
2
Publish Date
1993
Start Page
131
End Page
138

Sertraline attenuates hyperphagia in rats following nicotine withdrawal.

Chronic nicotine administration can decrease food consumption and body weight. Abrupt withdrawal from nicotine can cause the reverse effect, hyperphagia and rapid weight gain. In the current study, the efficacy of sertraline, a serotonin reuptake inhibitor, on nicotine withdrawal-induced hyperphagia and rapid weight gain was assessed in rats. Sertraline was found to be effective in reversing the increase in feeding that occurred after withdrawal from chronic nicotine administration. Sertraline caused a dose-related decrease in food consumption in control rats not given nicotine. Doses of 5 and 10 mg/kg/day caused significant decreases while 2.5 mg/kg/day caused a slight though nonsignificant decrease in food consumption. Rats in which nicotine was abruptly withdrawn after 3 weeks of administration showed a significant increase in food consumption relative to controls. This increase was eliminated by the high dose of sertraline (10 mg/kg/day), but not by the lower two doses (2.5 and 5 mg/kg/day). Water consumption was affected in a similar fashion. Body weight gain was also affected by sertraline. During the first week after nicotine withdrawal, rats rapidly gained weight, but sertraline attenuated this. The 10-mg/kg dose of sertraline significantly attenuated the nicotine withdrawal-induced weight gain. These results suggest that sertraline can counteract the hyperphagia and rapid weight gain associated with nicotine withdrawal, and might therefore be a useful adjunct to smoking cessation.

Authors
Levin, ED; Briggs, SJ; Christopher, NC; Rose, JE
MLA Citation
Levin, ED, Briggs, SJ, Christopher, NC, and Rose, JE. "Sertraline attenuates hyperphagia in rats following nicotine withdrawal." Pharmacol Biochem Behav 44.1 (January 1993): 51-61.
PMID
8430129
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
44
Issue
1
Publish Date
1993
Start Page
51
End Page
61

Sex-related spatial learning differences after prenatal cocaine exposure in the young adult rat.

Prenatal cocaine exposure in humans is associated with a variety of adverse neurobehavioral effects. In the rat, in utero cocaine exposure has been shown to elicit learning impairment during early postnatal development. However, little research has focused on the persistence of these behavioral disruptions. The current study examines the long-term effects of prenatal cocaine exposure on learning performance during young adulthood. Fetal cocaine exposure evoked differential effects in male and female rats on radial-arm maze learning performance. Cocaine-treated females showed significantly impaired choice accuracy during acquisition of radial-arm maze performance when compared to control females. In contrast, cocaine-treated males showed no impairment and in fact showed significantly improved performance on one measure of choice accuracy. For both sexes, this effect was apparent during the final third of acquisition. No evidence was found to suggest altered sensitivity to anticholinergic drugs. While both nicotinic and muscarinic cholinergic antagonists caused significant impairments in memory performance, control and cocaine-exposed rats were effected equally. Single doses of these drugs which caused moderate memory deficits were chosen for use in the current study. The entire dose range should be evaluated to determine the relative sensitivity of cocaine-exposed and control animals to these drugs. The results of this study indicate that there are cognitive effects of prenatal cocaine exposure which persist into adulthood and the sex of the offspring seems to be critical.

Authors
Levin, ED; Seidler, FJ
MLA Citation
Levin, ED, and Seidler, FJ. "Sex-related spatial learning differences after prenatal cocaine exposure in the young adult rat." Neurotoxicology 14.1 (1993): 23-28.
PMID
8361675
Source
pubmed
Published In
NeuroToxicology
Volume
14
Issue
1
Publish Date
1993
Start Page
23
End Page
28

SMOKING WHILE WEARING THE NICOTINE PATCH - IS SMOKING SATISFYING OR HARMFUL

Authors
WESTMAN, EC; LEVIN, ED; ROSE, JE
MLA Citation
WESTMAN, EC, LEVIN, ED, and ROSE, JE. "SMOKING WHILE WEARING THE NICOTINE PATCH - IS SMOKING SATISFYING OR HARMFUL." CLINICAL RESEARCH 40.4 (December 1992): A871-A871.
Source
wos-lite
Published In
Clinical Research
Volume
40
Issue
4
Publish Date
1992
Start Page
A871
End Page
A871

DERIVATION OF A LOGISTIC MODEL USING BASE-LINE CLINICAL INFORMATION TO PREDICT SUCCESS WITH THE NICOTINE PATCH IN SMOKING CESSATION

Authors
WESTMAN, EC; SIMEL, DL; LEVIN, ED; ROSE, JE
MLA Citation
WESTMAN, EC, SIMEL, DL, LEVIN, ED, and ROSE, JE. "DERIVATION OF A LOGISTIC MODEL USING BASE-LINE CLINICAL INFORMATION TO PREDICT SUCCESS WITH THE NICOTINE PATCH IN SMOKING CESSATION." CLINICAL RESEARCH 40.4 (December 1992): A811-A811.
Source
wos-lite
Published In
Clinical Research
Volume
40
Issue
4
Publish Date
1992
Start Page
A811
End Page
A811

Fetal nicotine exposure ablates the ability of postnatal nicotine challenge to release norepinephrine from rat brain regions.

Exposure of the fetus to nicotine is known to affect the function of noradrenergic pathways in the central nervous system. In the current study, synaptic mechanisms underlying the functional defects were evaluated in the offspring of pregnant rats given nicotine infusions of 2 mg/kg/day throughout gestation, administered by osmotic minipumps. At 30 days postpartum, norepinephrine levels in brain regions of the offspring were significantly reduced. More importantly, acute challenge with either 0.1 mg/kg or 0.3 mg/kg of nicotine evoked significant norepinephrine release from brain regions of control animals, but failed to do so in the fetal nicotine cohort. These results suggest that prenatal exposure to nicotine produces a deficit in subsequent noradrenergic responsiveness, deficits which may participate in behavioral and neuroendocrine abnormalities.

Authors
Seidler, FJ; Levin, ED; Lappi, SE; Slotkin, TA
MLA Citation
Seidler, FJ, Levin, ED, Lappi, SE, and Slotkin, TA. "Fetal nicotine exposure ablates the ability of postnatal nicotine challenge to release norepinephrine from rat brain regions." Brain Res Dev Brain Res 69.2 (October 23, 1992): 288-291.
PMID
1424104
Source
pubmed
Published In
Developmental Brain Research
Volume
69
Issue
2
Publish Date
1992
Start Page
288
End Page
291

The effect of halothane on cultured fibroblasts and neuroblastoma cells.

Halothane exposure over the cultured cells (100 and 1,000 ppm) caused a disruption of the pattern of actin distribution in both fibroblasts and neuroblastoma cells. Neuroblastoma cells exposed to halothane also lost microspikes; however, neurite elongation was not affected by halothane. The present study suggests that halothane induces the functional disruption of actin, resulting in an interference of normal neural development in vivo.

Authors
Uemura, E; Levin, ED
MLA Citation
Uemura, E, and Levin, ED. "The effect of halothane on cultured fibroblasts and neuroblastoma cells." Neurosci Lett 145.1 (September 28, 1992): 33-36.
PMID
1461563
Source
pubmed
Published In
Neuroscience Letters
Volume
145
Issue
1
Publish Date
1992
Start Page
33
End Page
36

Dopaminergic drugs reverse the impairment of radial-arm maze performance caused by lesions involving the cholinergic medial pathway.

Pharmacological studies have shown that both cholinergic and dopaminergic transmitter systems are crucial for optimal choice accuracy in the radial-arm maze and that these systems interact in a complex fashion. Lesion studies have provided evidence that the basal nuclear complex of the forebrain, the origin of cholinergic projections to the cerebral mantle, may be critical for the cholinergic modulation of learning and memory. We have shown that knife-cut lesions of the medial cholinergic pathway significantly impair radial-arm maze choice accuracy performance. The current study examined the effectiveness of D1 and D2 ligands in counteracting this lesion-induced deficit. The adverse effects of medial cholinergic pathway lesions were diminished or reversed by daily treatment with a D1 agonist (SKF 38393), a D2 agonist (LY 171555) or a D1 antagonist (SCH 23390), but were not affected by treatment with a D2 antagonist (raclopride). The three beneficial treatments have previously been found to attenuate the adverse effects of nictonic or muscarinic blockade on choice accuracy performance in the radial-arm maze. The finding that these dopaminergic drugs ameliorate the memory deficit caused by lesions involving the cholinergic medial pathway suggests the importance of interactions between cholinergic and dopaminergic systems in radial-arm maze performance. These results may provide leads for the development of novel therapeutic approaches for treating human disorders thought to result from cholinergic hypofunction.

Authors
McGurk, SR; Levin, ED; Butcher, LL
MLA Citation
McGurk, SR, Levin, ED, and Butcher, LL. "Dopaminergic drugs reverse the impairment of radial-arm maze performance caused by lesions involving the cholinergic medial pathway." Neuroscience 50.1 (September 1992): 129-135.
PMID
1357591
Source
pubmed
Published In
Neuroscience
Volume
50
Issue
1
Publish Date
1992
Start Page
129
End Page
135

Persistence of chronic nicotine-induced cognitive facilitation.

Nicotine has been found in a variety of species and behavioral paradigms to improve memory performance. The beneficial effect of nicotine has been seen after both acute and chronic administration. Interestingly, improved performance has been seen 24 h after acute injection and for at least 2 weeks after chronic administration. However, it is not clear from previous studies whether the persistence of the improved performance represents a true carryover of the drug effect or is due to the behavioral experience while under nicotine's effect. The current study was conducted to determine whether the facilitating effect of nicotine on learning and memory performance could be seen after withdrawal even if there was no behavioral training during the period of chronic nicotine administration. Rats were administered nicotine chronically for 3 weeks but were not tested during that time. Starting 1 week after withdrawal they were trained on a working memory paradigm in an eight-arm radial maze. The nicotine-treated rats started out at control-like levels of performance, but showed significantly faster learning as detected by three different measures of choice accuracy. By the final phase of testing the control subjects had caught up with the nicotine-treated rats. After the acquisition phase, acute challenges with the nicotinic and muscarinic antagonists, mecamylamine and scopolamine, did not elicit any differential effects in the nicotine-treated and control groups. The current study demonstrated that nicotine-induced cognitive facilitation persists for at least 4 weeks after withdrawal and does not depend upon behavioral test experience under the influence of the drug. The mechanism for this persisting effect is not currently understood.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Levin, ED; Briggs, SJ; Christopher, NC; Rose, JE
MLA Citation
Levin, ED, Briggs, SJ, Christopher, NC, and Rose, JE. "Persistence of chronic nicotine-induced cognitive facilitation." Behav Neural Biol 58.2 (September 1992): 152-158.
PMID
1456935
Source
pubmed
Published In
Behavioral and Neural Biology
Volume
58
Issue
2
Publish Date
1992
Start Page
152
End Page
158

Use of the lesion model for examining toxicant effects on cognitive behavior.

It is often beneficial to use a model to help understand unknown effects and relate those effects to an existing body of knowledge. In much of the early development of behavioral toxicology, the pharmacological model has served as a valuable theoretical guide, especially with regard to dosing and kinetic parameters. However, as with any model, it has certain limitations. The lesion model has complementary features which provide valuable insights into the behavioral effects of toxicants. This is particularly true for effects which persist long after the end of toxicant exposure. There is much literature describing effects of brain lesions on behavior. By comparing results from toxicology studies to those of lesion studies, one can take advantage of this trove of information to gain a better insight into the possible loci of toxic effects, and to identify tests which would be useful in further describing the nature of the toxic effects. In this article, we examine the theoretical and practical utility of the lesion model. Examples are given showing how it has proven useful in interpreting the cognitive effects of exposure of monkeys to lead and polychlorinated biphenyls (PCBs). These exposures produced syndromes that closely resemble the effects of lesions in the frontal cortex or limbic system.

Authors
Levin, ED; Schantz, SL; Bowman, RE
MLA Citation
Levin, ED, Schantz, SL, and Bowman, RE. "Use of the lesion model for examining toxicant effects on cognitive behavior." Neurotoxicol Teratol 14.2 (March 1992): 131-141.
PMID
1593987
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
14
Issue
2
Publish Date
1992
Start Page
131
End Page
141

Concurrent agonist-antagonist administration for the analysis and treatment of drug dependence.

Two key strategies for the treatment of drug dependence involve the use of agonists to substitute for the abused drug and the use of antagonists to block the reinforcing actions maintaining drug self-administration. A different strategy for the treatment of drug dependence is outlined, comprising the concurrent administration of an agonist and an antagonist. Concurrent administration of an agonist with an antagonist, in the proper ratio, should produce maximal occupancy of receptors and attenuation of the reinforcing actions of the abused drug. The addict would be relatively "insulated" from the reinforcing effects of the abused drug; at the same time the balance of agonist and antagonist effects is predicted to prevent withdrawal symptoms or intoxication resulting from an under- or over-stimulation of drug receptors. Advantages over the use of agonists alone and antagonists alone, and over mixed agonist-antagonist molecules, are discussed. Application of concurrent agonist-antagonist administration to the analysis of mechanisms underlying nondrug reinforcement and to the treatment of disorders involving receptor disregulation is also described.

Authors
Rose, JE; Levin, ED
MLA Citation
Rose, JE, and Levin, ED. "Concurrent agonist-antagonist administration for the analysis and treatment of drug dependence." Pharmacol Biochem Behav 41.1 (January 1992): 219-226. (Review)
PMID
1539072
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
41
Issue
1
Publish Date
1992
Start Page
219
End Page
226

ANIMAL-MODELS OF NICOTINE EFFECTS ON WEIGHT REGULATION

Authors
LEVIN, ED
MLA Citation
LEVIN, ED. "ANIMAL-MODELS OF NICOTINE EFFECTS ON WEIGHT REGULATION." HEALTH PSYCHOLOGY 11 (1992): 40-40.
Source
wos-lite
Published In
Health Psychology
Volume
11
Publish Date
1992
Start Page
40
End Page
40

Nicotinic systems and cognitive function.

Nicotinic acetylcholine receptors have been found to be important for maintaining optimal performance on a variety of cognitive tasks. In humans, nicotine-induced improvement of rapid information processing is particularly well documented. In experimental animals nicotine has been found to improve learning and memory on a variety of tasks, while the nicotinic antagonist mecamylamine has been found to impair memory performance. Nicotine has been found to be effective in attenuating memory deficits resulting from lesions of the septohippocampal pathway or aging in experimental animals. Nicotinic receptors are decreased in the cortex of patients with Alzheimer's disease. Preliminary studies have found that some aspects of the cognitive deficit in Alzheimer's disease can be attenuated by nicotine. Nicotine may prove to be useful therapeutic treatment for this and other types of dementia.

Authors
Levin, ED
MLA Citation
Levin, ED. "Nicotinic systems and cognitive function." Psychopharmacology (Berl) 108.4 (1992): 417-431.
PMID
1357713
Source
pubmed
Published In
Psychopharmacology
Volume
108
Issue
4
Publish Date
1992
Start Page
417
End Page
431

National working conference on smoking and body weight. Task Force 2: Methods of assessment, strategies for research.

Authors
Henningfield, JE; Obarzanek, E; Benowitz, NL; Hall, SM; Klesges, RC; Leischow, S; Levin, ED; Perkins, KA; Spring, B; Stitzer, M
MLA Citation
Henningfield, JE, Obarzanek, E, Benowitz, NL, Hall, SM, Klesges, RC, Leischow, S, Levin, ED, Perkins, KA, Spring, B, and Stitzer, M. "National working conference on smoking and body weight. Task Force 2: Methods of assessment, strategies for research." Health Psychol 11 Suppl (1992): 10-16. (Review)
PMID
1396498
Source
pubmed
Published In
Health Psychology
Volume
11 Suppl
Publish Date
1992
Start Page
10
End Page
16

Erratum: Use of the lesion model for examining toxicant effects on cognitive behavior (Neurotoxicol. Teratol. 14 (131-142) 1992)

Authors
Levin, E; Schantz, SL; Bowman, RE
MLA Citation
Levin, E, Schantz, SL, and Bowman, RE. "Erratum: Use of the lesion model for examining toxicant effects on cognitive behavior (Neurotoxicol. Teratol. 14 (131-142) 1992)." Neurotoxicology and Teratology 14.4 (1992): 298--.
Source
scival
Published In
Neurotoxicology and Teratology
Volume
14
Issue
4
Publish Date
1992
Start Page
298-
DOI
10.1016/0892-0362(92)90010-8

Nicotinic and muscarinic interactions and choice accuracy in the radial-arm maze.

Muscarinic acetylcholine (ACh) systems have long been known to be necessary for accurate performance in cognitive tests. Nicotinic ACh systems have been shown to be involved as well. However, there is only a limited amount of information concerning the interactions of these two branches of the ACh transmitter system. The current study was conducted to investigate the improvement in choice accuracy caused by muscarinic and nicotinic agonists and how it is affected by antagonists of these systems. Adult female Sprague-Dawley strain rats (N = 11) were trained on a working memory task in an 8-arm radial maze. Acute injections of the muscarinic and nicotinic agonists, pilocarpine (PILO, 1.0 mg/kg) and nicotine (NIC, 0.2 mg/kg), were made alone or in combination with the muscarinic and nicotinic antagonists, scopolamine (SCOP, 0.1 mg/kg) and mecamylamine (MEC, 10 mg/kg). NIC administration caused a significant improvement in choice accuracy compared with saline (p less than 0.01) and PILO caused a marginally significant improvement in choice accuracy (p less than 0.06). The combination of these nicotinic and muscarinic agonists did not cause an additive improvement. However, the improvement caused by either agonist was reversed by both nicotinic or muscarinic antagonists. This reversal was more complete for NIC than PILO despite the fact that NIC caused a greater improvement than PILO. These results suggest that muscarinic and nicotinic components of the ACh system, which are both important for cognitive function, interact in important ways. These interactions may be critical to consider when devising treatments for cognitive dysfunction associated with cholinergic hypofunction such as with Alzheimer's disease.

Authors
Levin, ED; Rose, JE
MLA Citation
Levin, ED, and Rose, JE. "Nicotinic and muscarinic interactions and choice accuracy in the radial-arm maze." Brain Res Bull 27.1 (July 1991): 125-128.
PMID
1933424
Source
pubmed
Published In
Brain Research Bulletin
Volume
27
Issue
1
Publish Date
1991
Start Page
125
End Page
128

Neurobehavioral toxicology of halothane in rats.

Halothane, a commonly used general anesthetic, is considered to be relatively safe for that purpose. Chronic exposure, however, has been found to cause long-lasting damage to neural structure and impairment of behavioral function. In rats, behavioral alterations are particularly evident after developmental exposure, but they can also be seen with adult exposure, especially when halothane is given during the period of neural regrowth following a brain lesion. The pattern of neural damage includes retarded synaptogenesis, impaired dendritic branching and disruption of organelle structure. The behavioral syndrome includes learning impairment, decreased exploratory behavior and decreased nociceptive reactivity. In general, the neural pathology is more pronounced and more easily discernible than the behavioral effects. Neural damage, particularly to the hippocampus, can be clearly seen at points when behavioral impairments have not been found. This demonstrates that in some cases changes in neural structure can be more sensitive indicators of toxic damage than behavioral dysfunction. Halothane exposure has proved to be quite useful as an experimental tool in the study of neural and behavioral recovery after brain lesions. For example, after unilateral entorhinal cortical lesions, behavioral recovery and reactive synaptogenesis occur contemporaneously. It has not been demonstrated whether the behavioral recovery is due to this reinnervation. Postlesion halothane exposure almost completely suppresses reactive synaptogenesis, however, behavioral recovery of T-maze alternation behavior occurs in the halothane-treated rats as well as in controls. This suggests that recovery of spatial performance after such a lesion is not due to recovery of innervation in the dentate, but to some other process such as other neural systems taking over the functions lost with the brain lesion. The studies reviewed highlight the dangers of halothane exposure, especially during development or when recovering from brain injury. They also provide a good case study for comparing the relative sensitivity of morphological and behavioral measures in toxicology and point to the potential use of halothane as an experimental tool for examining the relationships between neural structure and behavioral function.

Authors
Levin, ED; Uemura, E; Bowman, RE
MLA Citation
Levin, ED, Uemura, E, and Bowman, RE. "Neurobehavioral toxicology of halothane in rats." Neurotoxicol Teratol 13.4 (July 1991): 461-470. (Review)
PMID
1921926
Source
pubmed
Published In
Neurotoxicology and Teratology
Volume
13
Issue
4
Publish Date
1991
Start Page
461
End Page
470

The effects of smoking-related sensory cues on psychological stress.

Previous studies have shown that the sensory cues of cigarette smoking are important for smoking satisfaction and craving reduction. Sensory cues in the absence of pharmacological doses of nicotine have been found to be moderately satisfying and to reduce craving. The current study was conducted to determine if administration of the sensory cues of cigarette smoking with minimal nicotine would also provide relief from mild anxiety associated with anticipation of a difficult anagram test. This test has previously been shown to be sensitive to the anxiety relieving effects of cigarette smoking. Compared to the placebo control condition, the sensory condition caused a significant alleviation of the stress as measured by components of the Spielberger scale for anxiety. The addition of cigarette smoke containing 0.5 mg of nicotine to the sensory cues caused a slight though nonsignificant enhancement of the stress alleviation. These results demonstrate that sensory cues of smoking can provide similar effects as nicotine containing cigarettes with regard to stress alleviation. Previous studies had shown that sensory cues are important for the consumptive aspects of smoking (i.e., smoking satisfaction and craving reduction). The current study shows that sensory cues are important for other effects of smoking as well.

Authors
Levin, ED; Rose, JE; Behm, F; Caskey, NH
MLA Citation
Levin, ED, Rose, JE, Behm, F, and Caskey, NH. "The effects of smoking-related sensory cues on psychological stress." Pharmacol Biochem Behav 39.2 (June 1991): 265-268.
PMID
1946567
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
39
Issue
2
Publish Date
1991
Start Page
265
End Page
268

Inter-relationships between conditioned and primary reinforcement in the maintenance of cigarette smoking.

Research on smoking cessation has increasingly focussed on pharmacological aspects of nicotine and nicotine withdrawal. However, cigarette smoking also provides a characteristic set of sensory cues. These sensory aspects of smoking are important to address in that they may be potent conditioned reinforcing stimuli linked to the actions of nicotine. The repetition of the smoking act thousands of times per year by a moderately heavy smoker leads to a strong conditioned association between the sensory aspects of smoking (the putative CS) and the pharmacological effects of nicotine (the putative UCS). Strategies for disrupting CS-UCS associations may be useful in developing more effective smoking cessation treatments. These include: counterconditioning of the CS; presenting the CS alone; presenting the CS with the UCS but pharmacologically blocking the UCS; and presenting the CS and UCS in an unconnected fashion. The role of sensory cues in alleviating craving for cigarettes is discussed, and specific techniques for duplicating relevant sensory aspects of smoking without delivering significant doses of nicotine are described. The combination of nicotine and nicotinic antagonists to block primary reinforcement and hasten extinction of conditioned reinforcement is also considered.

Authors
Rose, JE; Levin, ED
MLA Citation
Rose, JE, and Levin, ED. "Inter-relationships between conditioned and primary reinforcement in the maintenance of cigarette smoking." Br J Addict 86.5 (May 1991): 605-609. (Review)
PMID
1859927
Source
pubmed
Published In
British Journal of Addiction
Volume
86
Issue
5
Publish Date
1991
Start Page
605
End Page
609

Interactive effects of D1 and D2 agonists with scopolamine on radial-arm maze performance.

Pharmacological blockade of muscarinic cholinergic (ACh) receptors has been found to impair choice accuracy in a variety of tasks including the radial-arm maze. The cognitive impairment caused by the muscarinic antagonist scopolamine is reversed by the dopaminergic (DA) antagonist haloperidol as well as the selective D1 antagonist SCH 23390. In the current study, interactions were studied between scopolamine and selective agonists of D1 (SCH 38393) and D2 (quinpirole) receptors. Surprisingly, the D1 agonist SKF 38393 was found to significantly alleviate the scopolamine-induced choice accuracy deficit. In contrast, the D2 agonist quinpirole was not found to significantly alter the effects of scopolamine on choice accuracy but did have supra-additive effects of increasing choice latency. Both the D1 agonist SKF 38393 and the D1 antagonist SCH 23390 have been found to reverse the choice accuracy deficit caused by scopolamine and the deficit resulting from lesions of the medial projection from the basal forebrain to the cortex. Possible mechanisms for these effects are discussed.

Authors
Levin, ED; Rose, JE
MLA Citation
Levin, ED, and Rose, JE. "Interactive effects of D1 and D2 agonists with scopolamine on radial-arm maze performance." Pharmacol Biochem Behav 38.2 (February 1991): 243-246.
PMID
1676165
Source
pubmed
Published In
Pharmacology Biochemistry and Behavior
Volume
38
Issue
2
Publish Date
1991
Start Page
243
End Page
246

Impairment of radial-arm maze performance in rats following lesions involving the cholinergic medial pathway: reversal by arecoline and differential effects of muscarinic and nicotinic antagonists.

Pharmacologic studies have indicated that accurate performance on the radial-arm maze depends upon the integrity of both nicotinic and muscarinic cholinergic neurotransmitter systems and that these systems interact in a complex fashion. Although numerous studies have suggested that pathways deriving from the basal nuclear complex of the forebrain are critical for the cholinergic modulation of learning and memory, most have focussed on the septohippocampal projection, and none have specifically targeted the medial or lateral systems. In Experiment 1, cortical knife cuts interrupting the medial cholinergic pathway were made at the level of the caudate-putamen nucleus. Such transections produced a robust but temporary disruption of choice accuracy performance in the radial-arm maze. Recovery of this behavior occurred within 10 days and before cholinergic fiber regeneration, suggesting that compensatory changes could have taken place in non-ablated neuronal circuits. In Experiment 2, daily postsurgical administration of arecoline, an agonist with predominantly muscarinic actions, was found to virtually eliminate the adverse behavioral effects of medial pathway transections, indicating that the deficit could be attributable, in part, to disruption of cholinergic projections. In Experiment 3, the effects of scopolamine, a muscarinic antagonist, and mecamylamine, a nicotinic antagonist, were examined in rats with medial cholinergic pathway transections after behavior had returned postsurgically to control levels. Although both drugs attenuated radial-arm maze performance before knife cuts, only scopolamine reduced choice accuracy following surgery. We conclude that the medial cholinergic pathway, particularly its nicotinic actions, plays an important role in cognitive function, at least as exemplified by radial-arm maze performance. Muscarinic mechanisms associated with other telencephalically projecting cholinergic networks, as well as possibly with the medial pathway itself, appear to operate interactively with nicotinic influences.

Authors
McGurk, SR; Levin, ED; Butcher, LL
MLA Citation
McGurk, SR, Levin, ED, and Butcher, LL. "Impairment of radial-arm maze performance in rats following lesions involving the cholinergic medial pathway: reversal by arecoline and differential effects of muscarinic and nicotinic antagonists." Neuroscience 44.1 (1991): 137-147.
PMID
1770993
Source
pubmed
Published In
Neuroscience
Volume
44
Issue
1
Publish Date
1991
Start Page
137
End Page
147

Long-term neurobehavioral effects of perinatal polychlorinated biphenyl (PCB) exposure in monkeys

In recent years, there has been growing concern about the potential long-term neurobehavioral effects of perinatal polychlorinated biphenyl (PCB) exposure. We have addressed this issue in a series of studies at the Harlow Primate Laboratory. Offspring of rhesus monkeys (Macaca mulatta) exposed to commercial PCB mixtures (Aroclor 1016 or Aroclor 1248) were tested on two-choice discrimination-reversal learning at 1.5 years of age and on delayed spatial alternation, a spatial learning and memory task, at four to six years of age. Deficits in performance were observed on both tasks. The deficit observed on delayed spatial alternation in Aroclor 1248-exposed monkeys was quite dramatic. The monkeys were tested for 80 test sessions, but were never able to achieve control levels of performance. This effect was observed when the monkeys were four to six years of age (young adulthood), even though they had not been exposed to PCBs since they were weaned at four months of age. The pattern of effects on both discrimination-reversal learning and delayed spatial alternation was suggestive of damage to the prefrontal cortex. © 1991.

Authors
Schantz, SL; Levin, ED; Bowman, RE
MLA Citation
Schantz, SL, Levin, ED, and Bowman, RE. "Long-term neurobehavioral effects of perinatal polychlorinated biphenyl (PCB) exposure in monkeys." Environmental Toxicology and Chemistry 10.6 (1991): 747-756.
Source
scival
Published In
Environmental Toxicology & Chemistry
Volume
10
Issue
6
Publish Date
1991
Start Page
747
End Page
756

Cholinergic-dopaminergic interactions in cognitive performance.

Both acetylcholinergic (ACh) and dopaminergic (DA) systems have been found to be crucial for the maintenance of accurate cognitive performance. In a series of studies examining those aspects of cognitive function revealed by the radial-arm maze, we have found that these two neurotransmitter systems interact in a complex fashion. Choice accuracy deficits in the radial-arm maze can be induced by blockade of either muscarinic- or nicotinic-ACh receptors. The choice accuracy deficit induced by blockade of muscarinic receptors with scopolamine can be reversed by the DA receptor blocker, haloperidol. The specific DA D1 blocker SCH 23390 also has this effect, whereas the specific D2 blocker raclopride does not, implying that it is D1 blockade that is critical for reversing the scopolamine effect. On the other hand, the choice accuracy deficit induced by nicotinic blockade with mecamylamine is potentiated by haloperidol. This effect is also seen with the D2 antagonist raclopride, but not with the D1 antagonist SCH 23390, implying that it is the D2 receptor which is important for the potentiation of the mecamylamine effect. The relevance of the D2 receptor for nicotinic actions on cognitive function is emphasized by the finding that the selective D2 agonist LY 171555 reverses the choice accuracy deficit caused by mecamylamine. Nicotinic and muscarinic blockade are synergistic in the deficit they produce. Antagonist doses subthreshold when given alone produce a pronounced impairment when given together. This latter deficit can be reversed by the D2 agonist LY 171555. These studies have outlined the complex nature of ACh-DA interactions with regard to cognitive function. Possible neural circuits for these interactions are discussed. The effectiveness of these selective DA treatments in reversing cognitive deficits due to ACh underactivation suggests a novel approach to treating cognitive dysfunction in syndromes such as Alzheimer's disease.

Authors
Levin, ED; McGurk, SR; Rose, JE; Butcher, LL
MLA Citation
Levin, ED, McGurk, SR, Rose, JE, and Butcher, LL. "Cholinergic-dopaminergic interactions in cognitive performance." Behav Neural Biol 54.3 (November 1990): 271-299. (Review)
PMID
2078161
Source
pubmed
Published In
Behavioral and Neural Biology
Volume
54
Issue
3
Publish Date
1990
Start Page
271
End Page
299

The use of flavor in cigarette substitutes.

Cigarette smokers identify flavor as an important factor in the pleasure derived from smoking and for their choice of cigarette brand. The issue of cigarette flavor has received a great deal of study by cigarette manufacturers but relatively little by academic investigators. The paucity of literature is particularly acute in terms of the importance of flavor in cigarette substitutes, which are used to help people to reduce or quit smoking. In the current study, five different types of flavors added to a plastic cigarette substitute were assessed in experienced smokers. There were two menthol-like flavors and three tobacco-like flavors. Two groups of smokers were tested: menthol smokers and "regular" (non-menthol) smokers. Both types of smokers liked the two menthol flavors significantly more than placebo and rated the menthol flavors and the cigarette flavor as significantly more satisfying than placebo. Craving was differentially reduced in the two groups of smokers. Menthol smokers showed a small reduction in craving with the placebo, with a significant enhancement of this reduction seen with the addition of the "EZ Quit" menthol flavor.

Authors
Levin, ED; Behm, F; Rose, JE
MLA Citation
Levin, ED, Behm, F, and Rose, JE. "The use of flavor in cigarette substitutes." Drug Alcohol Depend 26.2 (October 1990): 155-160.
PMID
2242716
Source
pubmed
Published In
Drug and Alcohol Dependence
Volume
26
Issue
2
Publish Date
1990
Start Page
155
End Page
160

Contrasting effects of centromedial and basolateral amygdaloid lesions on stress-related responses in the rat.

The effects of lesions in the centromedial and basolateral amygdala were examined using three different tests sensitive to the following stress-related responses: exploratory behavior, pain reactivity, and immune responses. The most clear-cut results were found with exploratory behavior. Rats with lesions of the centromedial amygdala tended to explore a radial-arm maze more quickly and entered more novel arms of the maze than controls. Those with lesions of the basolateral amygdala were generally too hesitant to explore at all. No significant differences were found between groups on measurements of natural killer cell activity. In tests of pain perception, rats in the control group displayed an analgesic response on the hot plate following an injection of the anxiogenic drug, RO 15-1788, whereas rats with centromedial lesions tended to exhibit a blunted response. These findings provide modest support for the view that the central and lateral regions of the amygdala play complementary roles in aversively motivated behaviors and in stress-related response patterns.

Authors
Grijalva, CV; Levin, ED; Morgan, M; Roland, B; Martin, FC
MLA Citation
Grijalva, CV, Levin, ED, Morgan, M, Roland, B, and Martin, FC. "Contrasting effects of centromedial and basolateral amygdaloid lesions on stress-related responses in the rat." Physiol Behav 48.4 (October 1990): 495-500.
PMID
2075198
Source
pubmed
Published In
Physiology & Behavior
Volume
48
Issue
4
Publish Date
1990
Start Page
495
End Page
500

Development of a citric acid aerosol as a smoking cessation aid.

The satisfaction derived from smoking depends not only on the pharmacological effects of nicotine but also the sensory stimulation from smoke inhalation, particularly the tracheal 'scratch'. In a previous study, we found that a citric acid aerosol produces a tracheal 'scratch' and provides some of the same satisfaction as cigarette smoke. In the present study, we evaluated a new pocket-sized device for delivering a citric acid aerosol and examined some of the important variables for providing a satisfying substitute for cigarettes. In the first experiment, volunteers who smoked at least 10 cigarettes per day compared a citric acid aerosol (either alone or with flavor additives) to a cigarette and a placebo. The addition of cigarette smoke flavor was found to best enhance the satisfaction provided by the citric acid aerosol. In the second experiment, smokers were given compact citric acid inhalers to use throughout 8 h of cigarette deprivation. The degree of satisfaction was highly correlated with the intensity of throat sensation provided by the aerosol. This citric acid aerosol inhaler may provide a useful tool for smokers while trying to quit smoking.

Authors
Levin, ED; Rose, JE; Behm, F
MLA Citation
Levin, ED, Rose, JE, and Behm, F. "Development of a citric acid aerosol as a smoking cessation aid." Drug Alcohol Depend 25.3 (June 1990): 273-279.
PMID
2189719
Source
pubmed
Published In
Drug and Alcohol Dependence
Volume
25
Issue
3
Publish Date
1990
Start Page
273
End Page
279

Transdermal nicotine facilitates smoking cessation.

The efficacy of a transdermal nicotine patch in facilitation of smoking cessation was evaluated in a randomized double-blind trial. Sixty-five smokers who were highly dependent on cigarettes participated in the study, which included a behavioral smoking-cessation program. The rates of continuous abstinence were significantly higher in the nicotine group both initially (55% versus 34%) and at 3 weeks (18% versus 6%). Certain smoking withdrawal symptoms, including negative affect and hypoarousal, were effectively relieved by the nicotine patch. There was a trend toward a reduction in cigarette craving, whereas hunger and habit withdrawal symptoms were not affected. The main side effect associated with the nicotine patch was skin irritation. These findings suggest that a nicotine skin patch may be a useful aid to smoking cessation; however, the combination of other techniques with nicotine replacement may provide a more effective treatment for symptoms such as craving for cigarettes.

Authors
Rose, JE; Levin, ED; Behm, FM; Adivi, C; Schur, C
MLA Citation
Rose, JE, Levin, ED, Behm, FM, Adivi, C, and Schur, C. "Transdermal nicotine facilitates smoking cessation." Clin Pharmacol Ther 47.3 (March 1990): 323-330.
PMID
2178852
Source
pubmed
Published In
Clinical Pharmacology & Therapeutics (Nature)
Volume
47
Issue
3
Publish Date
1990
Start Page
323
End Page
330

Chronic nicotine and withdrawal effects on radial-arm maze performance in rats.

Rats were tested for choice accuracy in an eight-arm radial maze during and after chronic administration of nicotine via subcutaneously implanted glass and Silastic capsules. Nicotine administration significantly improved choice accuracy relative to controls. The effect gradually became apparent over the first 2 weeks of exposure and persisted through the third week. Surprisingly, the significant facilitation of the nicotine-treated rats relative to controls continued for 2 weeks after the end of nicotine administration. No effects of nicotine were seen on choice latency or the strategy to make adjacent arm entries.

Authors
Levin, ED; Lee, C; Rose, JE; Reyes, A; Ellison, G; Jarvik, M; Gritz, E
MLA Citation
Levin, ED, Lee, C, Rose, JE, Reyes, A, Ellison, G, Jarvik, M, and Gritz, E. "Chronic nicotine and withdrawal effects on radial-arm maze performance in rats." Behav Neural Biol 53.2 (March 1990): 269-276.
PMID
2331235
Source
pubmed
Published In
Behavioral and Neural Biology
Volume
53
Issue
2
Publish Date
1990
Start Page
269
End Page
276