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）：与药物调节，渴望和复发有关的神经回路与涉及自然奖励的人重叠。最近，已经确定了Orexin/dypocretin（ORX/HCRT）系统，以调节一系列生理过程，包括喂养，能量代谢和唤醒，并已被证明是通过滥用药物招募的。 ORX/HCRT神经元主要位于下丘脑（LH）中，积累的证据表明这些神经元在药物成瘾中的重要作用。这些ORX/HCRT神经元向丘脑（PVT）的室室核项目投射，该区域已被鉴定为从LH接收预测，处理信息，然后调节中毛和外部丘脑外压力系统的“路站”。虽然不认为是“可卡因寻求可卡因电路”的一部分，但证据表明，PVT在奖励功能的调节中，尤其是指导性行为。重要的是，已经检测到可卡因寻求可卡因行为与PVT激活之间的相关性，但在自然而然的寻求奖励行为的情况下没有检测到。这表明可卡因失调PVT中的神经传递。利用我们的发现，我们假设在重复使用可卡因后，ORX/HCRT系统在调解寻求虐待药物与寻求自然奖励的滥用药物方面具有优惠的作用。该建议旨在研究通过专注于PVT中的ORX/HCRT传播作为一种新型神经基质的神经生物学基础，这可能是一种新型神经底物，可能导致可卡因寻求可卡因的明显强迫性质，而与自然奖励的行为相对于自然奖励的行为，而自然奖励对生存，健康和“健康” HeDonic Pursuits。具体而言，该提案将（i）在行为上表征PVT在可卡因寻求方面的特定含义，（ii）研究可卡因诱导的ORX/HCRT传播中可卡因诱导的神经塑性变化，并且（iii）研究了失调的ORX/HCRT-PVT对Mesolimbic系统的影响。