The long-term objective of the project is to understand the basic brain mechanisms underlying cocaine addiction, in particular, relapse which is probably the most challenging issue facing the current treatment of cocaine addiction. Exposure to cocaine-conditioned stimuli (CSs) can evoke unmanageable motivation even after long periods of abstinence to drive cocaine-seeking behavior and ultimately, relapse. Although rapid progress has been made in understanding how the CSs act on the brain circuits to sustain or reinforce already- initiated cocaine-seeking behavior by using extinction/reinstatement models, advances in understanding the neurobiological mechanisms underlying the incentive-motivational property of cocaine CSs, which plays a critical role in initiating and driving cocaine-seeking behavior, are hindered due to lack of appropriate animal models. This proposal aims to advance our understanding on the neural mechanisms underlying the conditioned incentive-motivational effects of cocaine-predicting CSs on relapse to cocaine-seeking behavior. Emerging evidence indicates that the mesocortical dopamine (DA) circuit may be critically involved in these effects. We hypothesize that the incentive-motivational effects of cocaine CSs critically depend upon activation of the mesocortical DA circuit by the CSs and moreover, such activation depends on glutamate input to the ventral tegmental area and DA input to the prefrontal cortex (PFC). One obstacle in studying the incentive- motivational effects of drug CSs is that the current animal models can not differentiate conditioned incentive- motivational effects of CSs from other conditioned effects such as conditioned reinforcing and automatic response-eliciting effects. To fill this gap, a novel animal model is proposed here based on the Pavlovian-to- instrumental transfer paradigm. Using this model we propose to test our hypothesis with integrated studies of electrophysiology and pharmacology of cocaine-seeking behavior reinstated by cocaine-predicting CSs. One distinctive feature of the proposed studies is that neuronal activity in the PFC will be monitored while animals are performing cocaine-seeking behavior during the CS-induced reinstatement. Simultaneous monitoring of neuronal activity and behavior provides a powerful tool to study the neuronal mechanisms of the behavior. In addition, by studying the effects on the reinstatement of receptor-specific antagonists directly microinjected into the mesocortical DA circuit, we will identify the molecular mechanisms involved in this process. Together, these studies will not only provide a much needed animal model but will shed light on the neural substrates, receptor systems, and neuronal mechanisms underlying the conditioned incentive-motivational effects of cocaine-predicting CSs. Such information will ultimately contribute to development of new anti-addiction therapies.Drug addiction is a chronic brain disease which exerts a heavy burden on drug addicts, family, and society. One major challenge facing current treatment of the disease is a high rate of relapse even after long periods of abstinence. This proposal aims to understand the basic brain mechanisms underlying relapse and therefore, will provide important information on how we can manipulate the brain processes to prevent or minimize relapse.