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.