Hypocretin/Orexin Regulation of Dopamine Signaling and Cocaine Reinforcement

下丘脑分泌素/食欲素对多巴胺信号传导和可卡因强化的调节

• 批准号: 9196339
• 负责人: Rodrigo A. España
• 金额: $ 31.11万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9196339
• 关键词: Acute; Affect; Area; Arousal; Attenuated; Behavior; Behavioral; Brain; Chronic Disease; Cocaine; Cocaine Dependence; Cues; Dependovirus; Dopamine; Dopamine Agonists; Dose; Drug Design; Genes; Genetic; Hypothalamic structure; Lateral; Lead; Literature; Mediating; Motor Activity; Nature; Neurons; Neuropeptides; Nucleus Accumbens; Peptides; Pharmacology; Pharmacotherapy; Process; Psychological reinforcement; Psychostimulant dependence; Publishing; Rattus; Regulation; Reinforcement Schedule; Research; Rewards; Sedation procedure; Self Administration; Signal Transduction; Sleep; System; Techniques; Testing; Therapeutic; Ventral Tegmental Area; Virus; Work; addiction; base; behavioral response; cell type; cocaine use; design; dopamine system; dopaminergic neuron; experimental study; feeding; gamma-Aminobutyric Acid; hypocretin; insight; interdisciplinary approach; knock-down; mesolimbic system; motivated behavior; neurochemistry; neuromechanism; neurotransmission; non-drug; novel; novel therapeutics; orexin A receptor; permissiveness; public health relevance; receptor; response; small hairpin RNA; tool

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.

描述（由申请人提供）：可卡因成瘾是一种慢性疾病，目前尚无获批的药物治疗。鉴于大量文献暗示中脑边缘多巴胺（DA）系统在可卡因的强化作用中，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，DA为基础的治疗往往是无效的或无法忍受的，并可能有滥用的潜力本身。下丘脑泌素/食欲素（hypocretins/orexins，HCRT）是一种参与调节觉醒、运动活动和各种动机性行为的神经肽。最近，HCRT系统也被证明可以通过DA丰富的腹侧被盖区的作用来影响可卡因强化。例如，我们已经表明，破坏腹侧被盖区的HCRT神经传递降低了可卡因的强化作用，并减弱了可卡因诱导的多巴胺在延髓核内的升高。基于这些和其他的观察，我们假设HCRT系统施加一个宽容的，兴奋性的影响，提高DA音调，并最终支持可卡因自我管理。因此，当HCRT信号传导被破坏时，对DA活性的兴奋性影响就会减弱，可卡因的自我给药就会减少。为了进一步表征HCRT系统调节DA信号传导和可卡因强化的程度，拟议的研究将采用多学科方法，使用复杂的行为，神经化学和病毒介导的基因操作技术。研究将审查：1）HCRT 1受体上的HCRT信号传导在基线、非药物条件下对丘脑核中DA信号传导的调节的贡献程度; 2）HCRT拮抗剂后可卡因自我给药的改变是否与镇静增加相关的关键问题; 3）HCRT信号传导在可卡因自我给药期间改变线索诱发和自发DA信号传导的程度;和4）使用病毒介导的HCRT受体敲低，确定腹侧被盖区（DA对GABA）中表达HCRT受体的神经元参与DA信号传导和对可卡因的行为反应的调节。这项工作的完成将提供信息在何种程度上药理学和遗传HCRT操作改变DA信号在基线条件下，并在响应可卡因和这些行动在何种程度上影响可卡因的增强效果。此外，这些研究将提供深入了解成瘾过程的神经机制，并可能为治疗可卡因成瘾的新药物疗法提供基础。