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
Ashare, Rebecca L; Lerman, Caryn; Cao, Wen et al. (2016) Nicotine withdrawal alters neural responses to psychosocial stress. Psychopharmacology (Berl) 233:2459-67
Forcelli, Patrick A; Turner, Jill R; Lee, Bridgin G et al. (2016) Anxiolytic- and antidepressant-like effects of the methadone metabolite 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP). Neuropharmacology 101:46-56
Schnoll, Robert A; Hitsman, Brian; Blazekovic, Sonja et al. (2016) Longitudinal changes in smoking abstinence symptoms and alternative reinforcers predict long-term smoking cessation outcomes. Drug Alcohol Depend 165:245-52
Strasser, Andrew A; Souprountchouk, Valentina; Kaufmann, Amanda et al. (2016) Nicotine Replacement, Topography, and Smoking Phenotypes of E-cigarettes. Tob Regul Sci 2:352-362
Perkins, Kenneth A; Karelitz, Joshua L; Michael, Valerie C et al. (2016) Initial Evaluation of Fenofibrate for Efficacy in Aiding Smoking Abstinence. Nicotine Tob Res 18:74-8
Ashare, R L; Kimmey, B A; Rupprecht, L E et al. (2016) Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers. Transl Psychiatry 6:e713
Lee, Bridgin G; Anastasia, Agustin; Hempstead, Barbara L et al. (2015) Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice. Nicotine Tob Res 17:1428-35
Falcone, M; Bansal-Travers, M; Sanborn, P M et al. (2015) Awareness of FDA-mandated cigarette packaging changes among smokers of 'light' cigarettes. Health Educ Res 30:81-6
Jhanjee, Sonali; Jain, Raka; Jain, Veena et al. (2015) Evaluating the Effects of Varenicline on Craving, Withdrawal, and Affect in a Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Varenicline for Smokeless Tobacco Dependence in India. J Psychoactive Drugs 47:325-30
Jain, Raka; Jhanjee, Sonali; Jain, Veena et al. (2015) Biochemical Validation of Self-Reported Smokeless Tobacco Abstinence among Smokeless Tobacco Users: Results from a Clinical Trial of Varenicline in India. J Psychoactive Drugs 47:331-5

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