Cocaine-induced Changes of Mesocorticolimbic Circuitry and Drug-seeking Behavior

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DESCRIPTION (provided by applicant): Cocaine dependence is a severe health problem with significant medical and societal impact. Minimal progress has been made towards developing effective treatments for cocaine addiction, and relapse rates for abstinent users remain high. A critical role for stress in the development and persistence of addiction has been reported over the past several years. Stress is one of the most commonly reported precipitants of drug abuse and is one of the major causes of relapse to drug-taking. However, the mechanisms by which stress exerts such a powerful influence over addictive processes are not well understood. Animal models of relapse have demonstrated strong similarities in the effects of stress and drugs of abuse on the midbrain dopaminergic system of the brain, a pathway most commonly implicated in the initiation of drug-taking and the progression to advanced stages of addiction. Exposure to drugs of abuse renders the dopaminergic systems of the brain more responsive to stress exposure, and indicates that neuroplasticity in the afferent regulation of dopamine neurons may be a mechanism by which stress comes to exert control over behavior in the addicted individual. However, the afferents involved in such regulation, and the changes that they undergo during the development of addiction, have yet to be identified. The current proposal seeks to precisely define the neurocircuitry involved in stress-induced reinstatement, identify alterations in the afferent regulation of the dopamine system, and investigate how such systems may influence drug seeking behavior in an animal model of relapse. The technical training encompassed by this proposal will build a foundation for more long-term multidisciplinary investigations into how stress and psychostimulant exposure interact to promote drug-seeking behavior. My training thus far has equipped me with the behavioral and electrophysiological skills necessary to initiate such investigations. The present career development proposal will extend my previous training and allow novel application of these techniques to significant issues in the field of addiction. Further, I will develop experience in innovative techniques, including viral tract tracing and optogenetics, which will give me the skill necessary to establish a research program that utilizes a comprehensive multidisciplinary approach to address questions of great importance in the study of addiction and motivated behavior. Issues examined in this proposal and in future studies will advance our understanding of the role of stress in addiction, as well as facilitate approaches for the successful treatment o addiction.