Role of Orexin/Hypocretin in cocaine-seeking behavior

描述(申请人提供)：涉及药物条件反射、渴求和复发的神经回路与涉及自然奖赏的神经回路重叠。最近，增食欲素/下丘脑皮质激素系统(Orx/Hcrt)被发现调节一系列生理过程，包括摄食、能量代谢和唤醒，并被证明是被滥用药物招募的。Orx/Hcrt神经元主要位于下丘脑外侧区，越来越多的证据表明这些神经元在药物成瘾中起着重要作用。这些Orx/Hcrt神经元投射到丘脑室旁核(PVT)，该区域被认为是一个“中转站”，接受来自黄体生成素的投射，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“寻找可卡因回路”的一部分，但证据表明，PVT总体上参与了奖赏功能的调节，特别是与药物有关的行为。重要的是，已经检测到寻求可卡因行为和激活PVT之间的相关性，但在自然寻求奖励行为的情况下没有相关性。这表明可卡因扰乱了PVT内的神经传递。根据我们的发现，我们假设在反复使用可卡因后，Orx/Hcrt系统在调节药物滥用寻求与自然奖赏寻求方面获得了优先作用。这项建议旨在研究慢性易复吸的神经生物学基础，重点关注PVT中Orx/Hcrt的传递，作为一种新的神经底物，可能导致可卡因寻求的明显强迫性质，而不是对生存、福祉和“健康”享乐追求至关重要的自然奖励所激发的行为。具体地说，这项建议将(I)在行为学上表征PVT在寻找可卡因中的具体含义，(Ii)研究可卡因诱导的Orx/Hcrt传递中的神经可塑性变化，以及(Iii)研究异常的Orx/Hcrt-PVT传递对中脑边缘系统的影响。

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.