This application is in response to RFA: DA-04-002 "Neuroimaging the Effects of Drugs of Abuse on the Development of the Human Nervous System". Cigarette smoking is a major public health problem that most often begins in adolescence and has a variety of serious negative consequences. Studies in animals and humans suggest that prolonged tobacco use causes neuroadaptation that accompanies the transition from use to dependence. Evidence also suggests that adolescent use of nicotine and other drugs of abuse may induce stronger effects on the systems sub-serving plasticity and cognition than in adults, consequently leading to more severe dependence-related behaviors. However, there are no clinical studies that have systematically examined this issue in youngsters. This proposal seeks to identify characteristics of brain function that can predict the risk for development of nicotine dependence (ND) in adolescents. It employs a prospective design and utilizes functional magnetic resonance imaging (fMRI) to identify possible abnormalities in the reactivity of specific brain regions to cognitive challenges in youth at high- and low-risk for ND. We hypothesize that altered responsivity of the brain circuits involved in motivational-reward processes to cognitive stimuli will be related to the development of ND in a longitudinal study and that the observed brain changes are more prominent in the high-risk group. The adolescents also will participate in follow-up studies of fMRI studies (after the onset of ND in those who develop it) to determine if, and to what extent, changes in brain function occur as a consequence of ND by comparing the baseline and follow-up measurements. The longitudinal design will distinguish pre-existing vulnerability markers for smoking and ND from changes in brain function due to chronic smoking. Distinction between premorbid factors and sequelae has implications for primary prevention and treatment programs. The high-risk group will consist of adolescents with depression, and the low-risk group will be comprised of youth without psychiatric illness. Studies in adolescents and adults have indicated that depression increases the risk for smoking. Also, data from adults suggest that depressed patients have more severe ND than their non-depressed counterparts, and a tendency for greater difficulty with smoking cessation and increased risk for relapse of depressive episodes during attempts to quit. The underlying mechanisms linking these two disorders are not well understood, thereby limiting the development of effective treatments. A systematic examination of the inter-relationships between depression and brain responsivity and the association of these two entities with vulnerability for ND and clinical course of depression will aid in the development of evidence-based algorithms for the diagnosis and treatment of individual patients with these disorders.