DESCRIPTION (provided by applicant): Tobacco smoking remains a leading cause of death and disability in the developed world. Many who wish to quit smoking are unable to do so. Although substantial advances have been made to identify neurobehavioral mechanisms underlying nicotine dependence, there is a great need to translate these findings into targeted, efficacious interventions, and to understand the mechanisms by which successful interventions exert their effects. Theoretical models and a growing empirical literature suggest that addictive disorders, including tobacco dependence, are characterized by mesolimbic hypersensitivity to smoking reward and related cues and hyposensitivity to nonsmoking rewards, particularly during the withdrawal that occurs during the early stages of a quit attempt. This dysregulated reward processing may represent a particular vulnerability for individuals with depressive symptoms that is likely to contribute to relapse and presents a promising target for intervention. The overarching goal of the research proposed in this application is to develop and evaluate a novel intervention that directly targets this reward processing imbalance by both a) decreasing smoking reinforcement through pretreatment with very low nicotine cigarettes (VLNC's) and b) increasing reinforcement from other non-drug rewards through behavioral activation (BA). The proposed research study has the following aims: 1) To examine the effects of BA + VLNC compared with VLNC only on mesolimbic reactivity and subjective sensitivity to smoking and monetary rewards among smokers with mild depressive symptoms; 2) To gather preliminary data on the effects of combined BA + VLNC on smoking cessation outcomes; and 3) To explore mediating and moderating effects of pre-and post-treatment brain function on smoking outcomes. The proposed research builds upon the Principle Investigator, Dr. Maggie Sweitzer's, previous experience and is closely aligned with her overarching career development goal of becoming an independent investigator with expertise in the development and evaluation of mechanistically-informed treatments for smoking cessation. Dr. Sweitzer is a clinical associate at Duke University Medical Center with expertise in behavioral pharmacology of smoking and functional neuroimaging. The primary training goals of this application are to gain skills in a) advanced neuroscience and neuroimaging methods; b) treatment development and evaluation; c) conducting clinical trials; and d) ethical and responsible conduct of research. The results of the proposed research and training plans will facilitate Dr. Sweitzer's development as an independent investigator and provide preliminary data for a future larger scale efficacy study.