In chronic smokers, abstinence from nicotine produces cognitive deficits that prompt relapse. Understanding the mechanisms that underlie these abstinence symptoms is critical to develop better treatments for nicotine addiction. The proposed project is designed to identify the brain mechanisms that underlie abstinence- induced cognitive symptoms in smokers using an integrated approach that combines neuroimaging, pharmacology, and genetics. We focus on the functional catechol-O-methyltransferase COMT (val158met) polymorphism, which has been implicated in both nicotine dependence and cognitive function. We have completed a pilot BOLD fMRI study which shows that smokers homozygous for the high activity val allele are more sensitive to the effects of an abstinence challenge on measures of cognition and brain function. This 3-year R01 application is designed to: (a) replicate and extend these results in a larger sample, and (b) perform a critical proof of mechanism experiment that tests the effects of the COMT inhibitor tolcapone on cognitive performance and brain function in abstinent smokers stratified by COMT val158met genotype. Specifically, we propose a within-subject double-blind cross-over neuroimaging study of short-term (13 days) tolcapone (vs. placebo) administration. Forty chronic smokers (20 with val/val genotypes and 20 with met/met genotypes) will undergo BOLD fMRI during 2 medication periods while performing a working memory task (N-back Task) and a sustained attention task (Continuous Performance Task): 1) after 3 days of monitored abstinence while on tolcapone, and 2) after 3 days of monitored abstinence while on placebo (medication order counterbalanced with a 2-week washout). A pre-treatment (baseline) scan is included to compare outcomes while smoking as usual to those while abstinent (on placebo). The primary outcome is medication effects (within subject) on task-related BOLD activation after 3 days of abstinence. Changes in behavioral performance and subjective symptoms will be examined in relation to brain activity changes. The proposed study will provide a critical mechanistic understanding of the role of COMT in nicotine dependence, thereby facilitating development of novel medications. Data generated from this study may further establish cognitive performance measures as important endophenotypes for nicotine dependence.

Public Health Relevance

This study will improve our understanding of the brain mechanisms that underlie abstinence-induced cognitive deficits which promote smoking relapse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA026849-02
Application #
7897616
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Kautz, Mary A
Project Start
2009-08-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$356,215
Indirect Cost
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ashare, Rebecca L; Falcone, Mary; Lerman, Caryn (2014) Cognitive function during nicotine withdrawal: Implications for nicotine dependence treatment. Neuropharmacology 76 Pt B:581-91
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
Ashare, Rebecca L; Wileyto, E Paul; Ruparel, Kosha et al. (2013) Effects of tolcapone on working memory and brain activity in abstinent smokers: a proof-of-concept study. Drug Alcohol Depend 133:852-6
Falcone, Mary; Smith, Ryan M; Chenoweth, Meghan J et al. (2013) Neuroimaging in psychiatric pharmacogenetics research: the promise and pitfalls. Neuropsychopharmacology 38:2327-37
Ashare, Rebecca L; Valdez, Jeffrey N; Ruparel, Kosha et al. (2013) Association of abstinence-induced alterations in working memory function and COMT genotype in smokers. Psychopharmacology (Berl) 230:653-62
Lerman, Caryn (2010) Preclinical data elucidate molecular and neural mechanisms of perinatal nicotine effects on neurodevelopment and behavior: translational opportunities and implications. Neuropsychopharmacology 35:2322-3
Lerman, Caryn; Audrain-McGovern, Janet (2010) Reinforcing effects of smoking: more than a feeling. Biol Psychiatry 67:699-701