Nicotine reward is an integral part of the addictive nature of nicotine, however, smoking and relapse to smoking are often motivated by the desire to alleviate negative affect and deficits in cognitive performance. Moreover, nicotine abstinence symptoms that promote smoking relapse are most evident in the first few days after quitting, suggesting this as a critical period to investigate neural mechanisms that may contribute to smoking relapse. To date, the underlying circuitry and mechanism(s) associated with alterations in emotional processing and learning and memory following nicotine deprivation have not been elucidated. Animal models for nicotine dependence are critical for investigating molecular mechanisms associated with this addiction. In particular, the mouse is a tractable model that allows for dissection of these mechanisms at a molecular and genetic level not afforded by human studies. Therefore, the overall goal of this project is to characterize novel phenotypes in mice to determine the effects of the early period of nicotine deprivation. Specifically, in Aim 1 we will determine the effects of nicotine deprivation on brain stimulation reward (BSR) and contextual learning and working memory. We hypothesize that chronic nicotine administration alters neural processes underlying affect and learning and memory such that when chronic exposure ceases, anhedonia and deficits in learning and memory will emerge. In order to increase our ability to develop novel therapeutic approaches to treat nicotine dependence, it is important to validate the use of our preclinical models and behavioral phenotypes with clinically effective medications. Therefore, in aim 2 we will evaluate the effects of systemic administration of varenicline (Chantix) on brain stimulation reward (BSR) and contextual learning and working memory following nicotine deprivation. As smokers often report stress relief as a motivating factor contributing to continued smoking behavior, we will investigate a role for stress factors (CRF) during the period of early nicotine deprivation. Thus, in aim 3, we will delineate the molecular mechanisms associated with nicotine deprivation through investigations of CRF by evaluating CRF receptor signaling mechanisms and a downstream target of this signaling cascade, CREB (cAMP response element binding protein). Together these studies will provide insights into the molecular mechanisms underlying nicotine deprivation. The complete understanding of these mechanisms would open new perspectives for the successful treatment of nicotine addiction.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA143187-05
Application #
8530981
Study Section
Special Emphasis Panel (ZDA1-RXL-E)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$298,592
Indirect Cost
$90,948
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Cole, Robert D; Poole, Rachel L; Guzman, Dawn M et al. (2015) Contributions of ?2 subunit-containing nAChRs to chronic nicotine-induced alterations in cognitive flexibility in mice. Psychopharmacology (Berl) 232:1207-17
Jain, Raka; Jhanjee, Sonali; Jain, Veena et al. (2014) A double-blind placebo-controlled randomized trial of varenicline for smokeless tobacco dependence in India. Nicotine Tob Res 16:50-7
Falcone, Mary; Wileyto, E Paul; Ruparel, Kosha et al. (2014) Age-related differences in working memory deficits during nicotine withdrawal. Addict Biol 19:907-17
Turner, J R; Ray, R; Lee, B et al. (2014) Evidence from mouse and man for a role of neuregulin 3 in nicotine dependence. Mol Psychiatry 19:801-10
Ashare, Rebecca L; Falcone, Mary; Lerman, Caryn (2014) Cognitive function during nicotine withdrawal: Implications for nicotine dependence treatment. Neuropharmacology 76 Pt B:581-91
Hussmann, G Patrick; DeDominicis, Kristen E; Turner, Jill R et al. (2014) Chronic sazetidine-A maintains anxiolytic effects and slower weight gain following chronic nicotine without maintaining increased density of nicotinic receptors in rodent brain. J Neurochem 129:721-31
Yohn, Nicole L; Turner, Jill R; Blendy, Julie A (2014) Activation of ?4?2*/?6?2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors. J Pharmacol Exp Ther 349:348-54
Ashare, Rebecca L; Schmidt, Heath D (2014) Optimizing treatments for nicotine dependence by increasing cognitive performance during withdrawal. Expert Opin Drug Discov 9:579-94
Goelz, Patricia M; Audrain-McGovern, Janet E; Hitsman, Brian et al. (2014) The association between changes in alternative reinforcers and short-term smoking cessation. Drug Alcohol Depend 138:67-74
Poole, Rachel L; Connor, David A; Gould, Thomas J (2014) Donepezil reverses nicotine withdrawal-induced deficits in contextual fear conditioning in C57BL/6J mice. Behav Neurosci 128:588-93

Showing the most recent 10 out of 69 publications