Role of Orexin/Hypocretin in cocaine-seeking behavior

描述（由申请人提供）：涉及药物条件反射、渴望和复发的神经回路与涉及自然奖励的神经回路重叠。最近，食欲素/下丘脑泌素（orexin/hocretin，Orx/Hcrt）系统已被确定为调节一系列生理过程，包括进食、能量代谢和唤醒，并且已被证明被滥用药物招募。Orx/Hcrt神经元主要位于外侧下丘脑（LH），越来越多的证据表明这些神经元在药物成瘾中起重要作用。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的“中途站”。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通常与奖赏功能的调节有关，特别是与药物相关的行为。重要的是，可卡因寻求行为和PVT激活之间的相关性已经被检测到，但在自然寻求奖励行为的情况下却没有。这表明，可卡因失调的神经传递内的PVT。利用我们的研究结果，我们假设，重复使用可卡因后，Orx/Hcrt系统获得了一个优先的作用，在调解药物滥用寻求与自然奖励寻求。这项建议的目的是研究慢性脆弱性复发的神经生物学基础，通过关注PVT中的Orx/Hcrt传递作为一种新的神经基质，可能是负责可卡因寻求的明显强迫性，而不是生存，幸福和“健康”享乐追求所必需的自然奖励所激发的行为。具体而言，该提案将（i）行为特征的特定含义的PVT可卡因寻求，（ii）调查可卡因引起的神经可塑性变化内的Orx/Hcrt传输和（iii）调查的影响失调的Orx/Hcrt-PVT传输的中脑边缘系统。

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.