In 1988, the US Surgeon General concluded that tobacco products are addictive and nicotine is the main pharmacological agent in tobacco responsible for tobacco's addictive nature. Despite over whelming evidence of the adverse health effects of smoking, it is estimated that 68.8 million Americans use tobacco products and 400,000 tobacco-related deaths occur in the United States each year. However, it is not completely understood why nicotine is addictive. One reason for this incomplete understanding of nicotine addiction may be that addiction is a complex disorder with many factors contributing to the disease. Possible factors that may contribute to nicotine addiction include genetics and learning. Many studies suggest that nicotine enhances learning. Specifically, the limbic area of the brain is involved in both learning and addiction and thus nicotine effects on this area may mediate cognitive influences on addiction. It is the hypothesis of this proposal that nicotine alters the function of the hippocampus during learning, producing a learned state that is different from learning in the absence of the drug, and that this learning may involve different patterns of cell signaling and gene activation than those activated during comparable learning without drug. The ability of nicotine to enhance learning processes may facilitate addiction by contributing to drug-context associations that could precipitate craving and relapse. In support of this, nicotine has been shown to enhance a long-lasting form of contextual fear conditioning, a type of classical conditioning that involves the hippocampus. Long-term memory storage is known to involve alteration in gene expression, and the proteins encoded by these induced genes, such as MAP kinases, result in long-lasting changes in neuronal function. Nicotine can also alter activation of MAP kinases. Proposed experiment will identify the nicotinic acetylcholinergic receptor subtypes, identify the neural site of action, and identify MAP kinases involved in the long-lasting enhancement of contextual fear conditioning by nicotine. Investigating the effects of nicotine on learning from the level of receptor activation to changes in cell signaling will enhance understanding of addiction and aid in development of treatments for nicotine addiction ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA017949-01A2
Application #
6969424
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Volman, Susan
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$280,141
Indirect Cost
Name
Temple University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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Kutlu, Munir Gunes; Connor, David A; Tumolo, Jessica M et al. (2018) Nicotine modulates contextual fear extinction through changes in ventral hippocampal GABAergic function. Neuropharmacology 141:192-200
Kutlu, Munir Gunes; Marin, Marie-France; Tumolo, Jessica M et al. (2018) Nicotine exposure leads to deficits in differential cued fear conditioning in mice and humans: A potential role of the anterior cingulate cortex. Neurosci Lett 673:142-149
Oliver, Chicora F; Kutlu, Munir Gunes; Zeid, Dana et al. (2018) Sex differences in the effects of nicotine on contextual fear extinction. Pharmacol Biochem Behav 165:25-28
Zeid, Dana; Kutlu, Munir Gunes; Gould, Thomas J (2018) Differential Effects of Nicotine Exposure on the Hippocampus Across Lifespan. Curr Neuropharmacol 16:388-402
Kutlu, Munir Gunes; Cole, Robert D; Connor, David A et al. (2018) Tyrosine receptor kinase B receptor activation reverses the impairing effects of acute nicotine on contextual fear extinction. J Psychopharmacol 32:367-372
Gitik, Miri; Holliday, Erica D; Leung, Ming et al. (2018) Choline ameliorates adult learning deficits and reverses epigenetic modification of chromatin remodeling factors related to adolescent nicotine exposure. Neurobiol Learn Mem 155:239-248
Kutlu, Munir Gunes; Tumolo, Jessica M; Cann, Courtney et al. (2018) Differential effects of ?4?2 nicotinic receptor antagonists and partial-agonists on contextual fear extinction in male C57BL/6 mice. Psychopharmacology (Berl) 235:1211-1219
Tumolo, Jessica M; Kutlu, Munir Gunes; Gould, Thomas J (2018) Chronic nicotine differentially alters spontaneous recovery of contextual fear in male and female mice. Behav Brain Res 341:176-180
Kutlu, Munir Gunes; Zeid, Dana; Tumolo, Jessica M et al. (2018) Pre-adolescent and adolescent mice are less sensitive to the effects of acute nicotine on extinction and spontaneous recovery. Brain Res Bull 138:50-55

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