Hypocretin/Orexin Regulation of Dopamine Signaling and Cocaine Reinforcement

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Project Summary: Psychostimulant addiction is a chronic disease and currently no approved pharmacotherapies exist for its treatment. Among the greatest challenges in the treatment of addiction is the prevention of relapse to drug use. In animals, periods of abstinence following drug use intensifies craving and motivation for drug, which has been associated with increased propensity for relapse. Recent advances suggest that alterations in mesolimbic dopamine systems during abstinent periods may be a critical component of the intensification of drug craving effect. Unfortunately, dopamine-based therapies are often ineffective or intolerable and may have abuse potential themselves. The hypocretins/orexins (HCRT) are hypothalamic neuropeptides that participate in the regulation of arousal, locomotor activity, and a variety of motivated behaviors. Over the past decade, the HCRT system has also been shown to influence drug reinforcement via actions in the dopamine-rich ventral tegmental area. For example, we have shown that disrupting HCRT neurotransmission within the ventral tegmental area reduces the reinforcing effects of cocaine and attenuates cocaine-induced elevations in dopamine within the nucleus accumbens. Recently we discovered a novel effect of acute HCRT disruption that causes long-lasting alterations in dopamine terminal sensitivity to cocaine and prevents increased motivation for cocaine following drug abstinence. To further examine the extent to which the HCRT system regulates dopamine signaling and cocaine reinforcement, the proposed research will employ a multidisciplinary approach using sophisticated behavioral, neurochemical, and genetic manipulation techniques. Studies will examine the utility of acute HCRT receptor 1 blockade on the development of intensified behavioral and dopaminergic responses to cocaine following a period of abstinence and whether these effects are dependent on dopamine neurons of the ventral tegmental area. Completion of this work will offer insight into the neural mechanisms underlying the addiction process and will provide the basis for a novel pharmacotherapy to treat cocaine addiction.