Hypocretin/Orexin Regulation of Dopamine Signaling and Cocaine Reinforcement

项目摘要： 精神兴奋剂成瘾是一种慢性疾病，目前还没有批准的药物治疗其 治疗戒毒治疗方面的最大挑战之一是预防吸毒复吸。 在动物中，药物使用后的禁欲期会加剧对药物的渴望和动机， 与复发倾向的增加有关。最近的进展表明，中脑边缘系统的改变 戒断期的多巴胺系统可能是药物渴望加剧的关键组成部分 效果不幸的是，多巴胺为基础的治疗往往是无效的或无法忍受的，并可能有滥用 潜力本身。下丘脑分泌素/食欲素（HCRT）是下丘脑神经肽，参与下丘脑的神经活动。 调节唤醒、运动活动和各种动机行为。在过去的十年里，HCRT 系统也被证明通过多巴胺丰富的腹侧神经元的作用影响药物强化。 被盖区例如，我们已经证明，在腹侧破坏HCRT神经传递， 被盖区减少可卡因的强化作用，并减弱可卡因诱导的 多巴胺在脑桥核内。最近，我们发现了急性HCRT中断的新效应， 导致对可卡因的多巴胺末端敏感性的长期改变，并阻止动机的增加 在戒毒后服用可卡因为了进一步研究HCRT系统调节 多巴胺信号和可卡因强化，拟议的研究将采用多学科的方法， 运用复杂的行为神经化学和基因操控技术研究将检查 急性HCRT受体1阻滞剂对强化行为和多巴胺能神经元损伤的作用 在一段时间的禁欲后对可卡因的反应以及这些作用是否依赖于多巴胺 腹侧被盖区的神经元。这项工作的完成将提供深入了解神经机制 这是成瘾过程的基础，并将为治疗可卡因的新药物疗法提供基础。 成瘾

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.