[unreadable] Despite ongoing efforts to understand its etiology and potential treatments, drug abuse persists as a severe social and economic dilemma in America. Our current understanding suggests that chronic drug use induces adaptations in neural circuitry that produce both positive (euphoric, pleasurable effects) and negative (withdrawal, dysphoria, drug craving) incentive for continued drug use despite unfavorable consequences. Understanding these changes as they occur over the course of drug exposure will greatly aid the development of effective treatment strategies. Animal models have elucidated many of the neuroadaptations that may occur in human drug abuse. Through two specific aims, the current proposal seeks to examine how gene expression is altered in a self-administration model of cocaine. The first aim will examine single-cell gene expression in VTA dopaminergic projections to the nucleus accumbens following acute and extended cocaine binges. Based in part on the results of Aim 1 as well as on previous gene expression studies, the second aim seeks to manipulate self-administration behavior through pharmacological agonists and antagonists as well as viral-mediated gene transfer. Overall, then, the proposed course of study will contribute to our understanding of drug addiction by examining how cocaine alters gene expression in a population of cells with known involvement in drug reinforcement. [unreadable] [unreadable] [unreadable] [unreadable]