Abstinence from smoking produces aversive symptoms that prompt relapse, often within the first week following a quit attempt. Our prior work has characterized these nicotine abstinence symptoms in smoking cessation pharmacotherapy trials and identified those relating to smoking relapse. Extending this work, we propose to elucidate brain and behavioral mechanisms underlying medication effects on key early abstinence symptoms using arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI), and blood oxygen level dependent (BOLD) functional MRI (fMRI). Varenicline, an a4p2 nicotinic acetylcholine receptor partial agonist, will be used as a model medication, based on its superior clinical efficacy.
The specific aims are: (1) to identify the neural substrates for varenicline effects on urges to smoke, using ASL perfusion MRI during a nicotine abstinent resting state, (2) To identify the neural substrates for varenicline effects on working memory during nicotine abstinence, using the N-back paradigm, and (3) To identify the neural substrates for varenicline effects on limbic reactivity to emotional stimuli during nicotine abstinence using a Face Emotion Identification fMRI paradigm. The study design is a within-subject double-blind crossover neuroimaging study of short-term (13 days) varenicline (vs. placebo) administration. Sixty treatmentseeking smokers will be scanned during 2 medication periods: (1) after 3 days of monitored abstinence while on varenicline, and (2) after 3 days of monitored abstinence while on placebo (medication order counterbalanced with a 2-week washout period). The primary outcomes are medication effects (within subject) on: (a) resting regional cerebral blood flow (rCBF) (ASL perfusion MRI), and (b) task-related BOLD activation (BOLD fMRI) after 3 days of abstinence. We will examine changes in behavioral performance and subjective symptoms in relation to brain activity changes. Following this investigation, all participants will be enrolled into a 12 week open-label varenicline trial, and we will explore associations of imaging data with clinical relapse. This research will contribute to pharmacotherapy development for nicotine dependence by: (a) providing a "neural fingerprint" against which future novel compounds can be compared, and (b) establishing the use neuroimaging as an early "surrogate marker" for medication response.

Public Health Relevance

This work will contribute to the development of better medications for nicotine dependence by increasing our understanding of early nicotine abstinence symptoms and how effective medications reverse these symptoms.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA143187-05
Application #
8530982
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
$237,237
Indirect Cost
$72,260
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

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