Tobacco use is a serious health problem in the United States: over 435,000 deaths each year are attributed to smoking, and although 42% of smokers attempt to quit each year, less than 6% are successful. These statistics suggest that current smoking cessation treatments are not adequate. One motivating factor that may contribute to both the maintenance of nicotine addiction and relapse is nicotine withdrawal effects. Withdrawal symptoms reported by smokers include insomnia, increased appetite, affective changes, and cognitive deficits. In fact, changes in cognition during abstinence predict relapse;suggesting that understanding the neural and genetic substrates underlying these changes could facilitate development of more efficacious treatments. Great advances have been made in understanding nicotine addiction but there are serious gaps in our knowledge of nicotine withdrawal. For instance, examination of the neurobiological substrates of nicotine withdrawal disruption of cognitive processes is limited and examination of genetic influences is nonexistent. A goal of this proposal is to identify the genetic and neurobiological substrates of nicotine withdrawal deficits in contextual conditioning, a cognitive process. This proposal will use traditional behavioral genetic techniques and genetically modified mice to achieve this goal. Characterizing the dynamics of nicotine withdrawal will further understanding of nicotine addiction and aid in understanding the relationship between the behavioral effects of nicotine and changes in receptor function and downstream processes. Identification of the genetic and neural substrates of nicotine withdrawal will aid development of new treatments for nicotine withdrawal symptoms and in the tailoring of treatments to produce the most effective results. In studies of smokers, it is clear that changes in cognitive processes during abstinence are an important component of nicotine withdrawal. One thing that is striking when examining the literature on animal models of withdrawal is the dearth of information on the genetic and neural substrates of nicotine withdrawal deficits in cognitive processes. This proposal will examine the pharmacology, the neurobiology, and the genetics of nicotine withdrawal disruption of contextual learning in mice. Identifying neurobiological and genetics factors that contribute to the effects of nicotine is important for understanding nicotine addiction and for developing novel treatments that could potentially be tailored by genotype to provide the most effective treatment.

Public Health Relevance

In studies of smokers, it is clear that changes in cognitive processes during abstinence are an important component of nicotine withdrawal. One thing that is striking when examining the literature on animal models of withdrawal is the dearth of information on the genetic and neural substrates of nicotine withdrawal deficits in cognitive processes. This proposal will examine the pharmacology, the neurobiology, and the genetics of nicotine withdrawal disruption of contextual learning in mice. Identifying neurobiological and genetics factors that contribute to the effects of nicotine is important for understanding nicotine addiction and for developing novel treatments that could potentially be tailored by genotype to provide the most effective treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA024787-03
Application #
7803692
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Volman, Susan
Project Start
2008-09-19
Project End
2013-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
3
Fiscal Year
2010
Total Cost
$371,830
Indirect Cost
Name
Temple University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Leach, Prescott T; Gould, Thomas J (2015) Thyroid hormone signaling: Contribution to neural function, cognition, and relationship to nicotine. Neurosci Biobehav Rev 57:252-63
Leach, Prescott T; Holliday, Erica; Kutlu, Munir G et al. (2015) Withdrawal From Chronic Nicotine Reduces Thyroid Hormone Levels and Levothyroxine Treatment Ameliorates Nicotine Withdrawal-Induced Deficits in Hippocampus-Dependent Learning in C57BL/6J Mice. Nicotine Tob Res 17:690-6
Gould, Thomas J; Leach, Prescott T (2014) Cellular, molecular, and genetic substrates underlying the impact of nicotine on learning. Neurobiol Learn Mem 107:108-32
Simmons, Steven J; Gould, Thomas J (2014) Involvement of neuronal ?2 subunit-containing nicotinic acetylcholine receptors in nicotine reward and withdrawal: implications for pharmacotherapies. J Clin Pharm Ther 39:457-67
Gould, Thomas J; Wilkinson, Derek S; Yildirim, Emre et al. (2014) Dissociation of tolerance and nicotine withdrawal-associated deficits in contextual fear. Brain Res 1559:1-10
Logue, Sheree F; Gould, Thomas J (2014) The neural and genetic basis of executive function: attention, cognitive flexibility, and response inhibition. Pharmacol Biochem Behav 123:45-54
Gould, Thomas J; Wilkinson, Derek S; Yildirim, Emre et al. (2014) Nicotine shifts the temporal activation of hippocampal protein kinase A and extracellular signal-regulated kinase 1/2 to enhance long-term, but not short-term, hippocampus-dependent memory. Neurobiol Learn Mem 109:151-9
Wilkinson, Derek S; Gould, Thomas J (2013) Withdrawal from chronic nicotine and subsequent sensitivity to nicotine challenge on contextual learning. Behav Brain Res 250:58-61
Wilkinson, Derek S; Turner, Jill R; Blendy, Julie A et al. (2013) Genetic background influences the effects of withdrawal from chronic nicotine on learning and high-affinity nicotinic acetylcholine receptor binding in the dorsal and ventral hippocampus. Psychopharmacology (Berl) 225:201-8
Turner, Jill R; Wilkinson, Derek S; Poole, Rachel Lf et al. (2013) Divergent functional effects of sazetidine-a and varenicline during nicotine withdrawal. Neuropsychopharmacology 38:2035-47

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