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

基本信息

批准号：
8438911
负责人：
Rodrigo A. España
金额：
$ 33.32万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8438911
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 cell type cocaine use design dopamine system dopaminergic neuron feeding gamma-Aminobutyric Acid hypocretin insight interdisciplinary approach mesolimbic system motivated behavior neurochemistry neuromechanism neurotransmission non-drug novel novel therapeutics public health relevance receptor research study response small hairpin RNA tool

项目摘要

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，目前尚无批准的药物治疗。鉴于广泛的文献涉及中脑膜多巴胺（DA）系统在可卡因的增强作用中，旨在治疗可卡因成瘾的药物通常针对DA系统。不幸的是，基于DA的治疗疗法通常是无效或无法忍受的，并且本身可能具有滥用潜力。低载染素/甲状腺素（HCRT）是参与唤醒，运动活性和各种动机行为的调节的神经肽。最近，HCRT系统还显示出通过在DA-DA-DA-DA-富腹侧对段区域的作用影响可卡因的增强。例如，我们已经表明，破坏腹侧对段区域内HCRT神经传递会降低可卡因的增强作用，并减轻可卡因诱导的伏源于DA中可卡因诱导的升高。基于这些和其他观察结果，我们假设HCRT系统具有宽松的兴奋性影响，从而增强了DA音调并最终支持可卡因自我给药。因此，当HCRT信号被破坏时，对DA活性的兴奋性影响会减少，可卡因自我给药会减少。为了进一步表征HCRT系统调节DA信号传导和可卡因增强的程度，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纵技术采用多学科方法。研究将检查：1）HCRT 1受体处的HCRT信号传导在基线基线，非药物条件下在伏隔核中调节DA信号的程度； 2）HCRT拮抗剂后可卡因自我给药的改变是否与镇静增加有关的关键问题； 3）HCRT信号在可卡因自我管理过程中改变提示引起的和自发的DA信号的程度； 4）确定使用病毒介导的HCRT受体的敲低的敲低的腹侧信号传导和对可卡因的行为反应调节DA信号传导和行为反应。这项工作的完成将提供有关药理学和遗传HCRT操作在基线条件下以及对可卡因的响应以及这些作用影响可卡因的增强作用的程度的程度的信息。此外，这些研究将提供有关成瘾过程基础的神经机制的洞察力，并可能为治疗可卡因成瘾的新药物疗法提供基础。