Hypocretin/Orexin Regulation of Dopamine Signaling and Cocaine Reinforcement

描述(申请人提供)：可卡因成瘾是一种慢性疾病，目前没有批准的药物疗法来治疗它。鉴于大量文献表明中脑边缘多巴胺(DA)系统与可卡因的强化作用有关，设计用于治疗可卡因成瘾的药物通常针对DA系统。不幸的是，以DA为基础的疗法往往无效或无法忍受，本身可能有滥用的可能性。下克隆素/食欲素(HCRT)是一种神经肽，参与觉醒、运动活动和各种动机行为的调节。最近，HCRT系统也被证明通过在富含DA的腹侧被盖区的作用来影响可卡因的强化。例如，我们已经证明，中断腹侧被盖区的HCRT神经传递会减少可卡因的增强效应，并减弱可卡因诱导的伏核内DA的升高。基于这些和其他观察，我们假设HCRT系统施加了一种允许的、兴奋的影响，增强了DA音调，最终支持可卡因的自我给药。因此，当HCRT信号中断时，对DA活动的兴奋性影响减弱，可卡因自我给药减少。为了进一步确定HCRT系统调节DA信号和可卡因强化的程度，拟议的研究将使用复杂的行为、神经化学和病毒介导的基因操作技术的多学科方法。研究将检查：1)在基线的非药物条件下，HCRT 1受体上的HCRT信号在多大程度上有助于调节伏核中的DA信号；2)HCRT拮抗剂后的可卡因自我给药的变化是否与增加镇静有关的关键问题；3)在可卡因自我给药过程中，HCRT信号在多大程度上改变了提示诱发的和自发的DA信号；以及4)确定腹侧被盖区(DA与GABA)中哪些表达HCRT受体的神经元参与了利用病毒介导的HCRT受体的敲除来调节DA信号和可卡因的行为反应。这项工作的完成将提供信息，说明在基线条件下和对可卡因的反应中，药物和遗传的HCRT操作在多大程度上改变了DA信号，以及这些行动在多大程度上影响了可卡因的强化效果。此外，这些研究将提供对成瘾过程潜在的神经机制的洞察，并可能为治疗可卡因成瘾的新药物疗法提供基础。

DESCRIPTION (provided by applicant): Cocaine addiction is a chronic disease and currently no approved pharmacotherapies exist for its treatment. Given the extensive literature implicating the mesolimbic dopamine (DA) system in the reinforcing effects of cocaine, drugs designed to treat cocaine addiction have often targeted DA systems. Unfortunately, DA-based therapeutics are often ineffective or intolerable and may have abuse potential themselves. The hypocretins/orexins (HCRT) are neuropeptides that participate in the regulation of arousal, locomotor activity, and a variety of motivated behaviors. Recently, the HCRT system has also been shown to influence cocaine reinforcement via actions in the DA-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 DA within the nucleus accumbens. Based on these and other observations, we hypothesize that the HCRT system exerts a permissive, excitatory influence that enhances DA tone and ultimately supports cocaine self-administration. Thus, when HCRT signaling is disrupted, excitatory influences on DA activity are diminished and cocaine self-administration is reduced. To further characterize the extent to which the HCRT system regulates DA signaling and cocaine reinforcement, the proposed research will employ a multidisciplinary approach using sophisticated behavioral, neurochemical, and virus-mediated gene manipulation techniques. Studies will examine: 1) the extent to which HCRT signaling at HCRT 1 receptors contributes to the regulation of DA signaling in the nucleus accumbens under baseline, non- drug conditions; 2) the critical issue of whether alterations in cocaine self-administration following HCRT antagonists are associated with increased sedation; 3) the extent to which HCRT signaling alters cue-evoked and spontaneous DA signaling during cocaine self-administration; and 4) determine which HCRT receptor- expressing neurons in the ventral tegmental area (DA vs. GABA) are involved in the regulation of DA signaling and behavioral responses to cocaine using virus-mediated knockdown of HCRT receptors. Completion of this work will provide information on the degree to which pharmacological and genetic HCRT manipulations alter DA signaling under baseline conditions and in response to cocaine and the extent to which these actions affect the reinforcing effects of cocaine. Additionally, these studie will offer insight into the neural mechanisms underlying the addiction process and may provide the basis for a novel pharmacotherapy to treat cocaine addiction.