Role of Orexin/Hypocretin in cocaine-seeking behavior

食欲素/下丘脑分泌素在可卡因寻求行为中的作用

• 批准号: 8484812
• 负责人: Remi Martin-Fardon
• 金额: $ 40.93万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484812
• 关键词: Abstinence; Accounting; Acetylcysteine; Address; Affect; Amygdaloid structure; Animals; Arousal; Behavior; Behavioral; Brain; Brain region; Cell Nucleus; Chronic; Cocaine; Cocaine Dependence; Drug Addiction; Energy Metabolism; Etiology; Extinction (Psychology); Feeding behaviors; Gene Activation; Globus Pallidus; Goals; Hippocampus (Brain); Hypothalamic structure; Immediate-Early Genes; Incentives; Laboratories; Lateral; Long-Term Effects; Measures; Medial; Mediating; Milk; Molecular; Motivation; Nature; Neurobiology; Neurons; Nucleus Accumbens; Pharmaceutical Preparations; Physiological Processes; Prefrontal Cortex; Recording of previous events; Recruitment Activity; Regulation; Relapse; Resistance; Rewards; Role; Self Administration; Signal Transduction; Stress; Structure of paraventricular nucleus of thalamus; Structure of terminal stria nuclei of preoptic region; System; Testing; Therapeutic; Ventral Tegmental Area; addiction; base; behavior influence; cocaine exposure; cocaine use; conditioning; craving; design; drug of abuse; drug seeking behavior; feeding; hedonic; hypocretin; information processing; insight; mRNA Expression; mesolimbic system; motivated behavior; neural circuit; neurochemistry; neurotransmission; new therapeutic target; novel; receptor function; reinforcer; relating to nervous system; research study; transmission process

DESCRIPTION (provided by applicant): Neural circuits implicated in drug conditioning, craving, and relapse overlap with those involved in natural reward. Recently, the orexin/hypocretin (Orx/Hcrt) system has been identified to regulate a range of physiological processes, including feeding, energy metabolism, and arousal, and has been shown to be recruited by drugs of abuse. Orx/Hcrt neurons are predominantly located in the lateral hypothalamus (LH), and accumulating evidence indicates an important role for these neurons in drug addiction. These Orx/Hcrt neurons project to the paraventricular nucleus of the thalamus (PVT), a region that has been identified as a "way- station" that receives projections from the LH, processes information, and then modulates the mesolimbic and extrahypothalamic stress systems. While not thought to be part of the "cocaine-seeking circuitry," evidence implicates the PVT in the modulation of reward function in general and drug-directed behavior in particular. Importantly, a correlation between cocaine-seeking behavior and activation of the PVT has been detected, but not in the case of natural reward-seeking behavior. This suggests that cocaine dysregulates the neurotransmission within the PVT. Capitalizing on our findings, we hypothesize that following repeated cocaine use, the Orx/Hcrt system acquires a preferential role in mediating drug of abuse seeking vs. natural reward seeking. This proposal is designed to study the neurobiological basis of chronic vulnerability to relapse by focusing on Orx/Hcrt transmission in the PVT as a novel neural substrate that may be responsible for the distinctly compulsive nature of cocaine seeking as opposed to behavior motivated by natural rewards essential for survival, well being, and "healthy" hedonic pursuits. Specifically, this proposal will (i) behaviorally characterize the specific implication of the PVT in cocaine seeking, (ii) investigate cocaine-induced neuroplastic changes within Orx/Hcrt transmission and (iii) investigate the effects of dysregulated Orx/Hcrt-PVT transmission on the mesolimbic system.

描述（由申请人提供）：涉及药物调节、渴望和复发的神经回路与涉及自然奖赏的神经回路重叠。最近，食欲素/下丘脑分泌素（Orx/Hcrt）系统已被确定可以调节一系列生理过程，包括进食、能量代谢和唤醒，并且已被证明可以被滥用药物招募。 Orx/Hcrt 神经元主要位于下丘脑外侧 (LH)，越来越多的证据表明这些神经元在药物成瘾中发挥着重要作用。这些 Orx/Hcrt 神经元投射到丘脑室旁核 (PVT)，该区域已被确定为“中转站”，接收来自 LH 的投射、处理信息，然后调节中脑边缘和下丘脑外应激系统。虽然不被认为是“可卡因寻求回路”的一部分，但有证据表明 PVT 与一般奖赏功能的调节有关，特别是与药物导向的行为有关。重要的是，已经检测到可卡因寻求行为与 PVT 激活之间的相关性，但在自然寻求奖励行为的情况下却没有。这表明可卡因使 PVT 内的神经传递失调。利用我们的研究结果，我们假设在重复使用可卡因后，Orx/Hcrt 系统在调解滥用药物寻求与自然奖励寻求方面获得优先作用。该提案旨在通过关注 PVT 中的 Orx/Hcrt 传递作为一种新型神经基质来研究慢性易复发性的神经生物学基础，这种新型神经基质可能导致可卡因寻求的明显强迫性质，而不是由自然奖励驱动的行为为了生存、福祉和“健康”的享乐追求。具体来说，该提案将（i）在行为上表征 PVT 在可卡因寻求中的具体含义，（ii）研究 Orx/Hcrt 传播中可卡因诱导的神经塑性变化，以及（iii）研究失调的 Orx/Hcrt-PVT 传播对可卡因寻求的影响。中脑边缘系统。