Hypocretinergic control of cocaine abuse

吸毒成瘾被认为是一种慢性疾病，也是许多其他疾病的危险因素， 紊乱为了更好地治疗成瘾和防止未来滥用非法药物，了解 成瘾行为的潜在机制临床和动物研究已经证实， 地位有助于确定人类和动物的奖赏阈值。食物限制性 增加对滥用药物的敏感性，而营养过剩则降低对药物的敏感性。但 大脑中调节代谢状态的回路是如何与奖赏回路相互作用的，这仍然是一个谜。的 外侧下丘脑（LH），一个整合来自不同大脑区域的广泛输入的中枢枢纽 编码代谢，行为和环境线索，是一个关键的大脑区域，以调节能量， 稳态和食物/药物奖励。具体地说，一组选择性的神经元专门合成 神经肽下丘脑泌素（hypocretin，Hcrt，又称食欲素）影响食物摄取，在食物奖赏中起重要作用 和毒瘾目前还不完全清楚Hcrt系统在电路层次中扮演什么角色 负责食物奖励和药物成瘾。我们和其他人最近的研究表明， 系统经历经验依赖性突触可塑性暴露于可卡因的动物，这导致 我们的总体假设是，Hcrt细胞中经验依赖性突触可塑性的表达 有助于动物成瘾行为的发展。如果这是真的， Hcrt神经元中的突触可塑性可能有助于动物对成瘾行为的易感性。 基于我们以前的研究，我们假设代谢/能量状态可能决定对 奖励物质通过调节动物Hcrt神经元的活性和可塑性而发挥作用。本申请中 源于R21赠款，我们将开始通过确定是否超过- 营养或慢性能量缺乏改变了可卡因触发Hcrt系统可塑性的能力， 分子（Hcrt-IRES-Cre小鼠和DREADD）、细胞（电生理学和EM研究）和 行为（可卡因条件性位置偏好）方法。三个具体目标是：1）确定 营养过剩是否会引起Hcrt神经元的适应性变化，这是药物损伤所必需的， 寻找动物的行为。2)测试慢性能量缺乏是否导致Hcrt适应 神经元，这有利于动物的药物奖励的表达。3)为了探究营养过剩是否 和能量缺乏诱导的Hcrt神经元的适应性改变导致靶区域的反应， 当动物暴露于可卡因时。我们的长期目标是弥合我们 目前对成瘾的理解，并弥合临床研究和基础研究之间的差距， Hcrt系统在成瘾行为中的作用，这是一个迄今为止还没有很好探索的研究领域。

Drug addiction has been considered a chronic disease and a risk factor for many other diseases and disorders. To better treat addiction and prevent future abuse of illicit drugs, it is essential to understand the mechanisms underlying addictive behaviors. Clinical and animal studies have established that the metabolic status contributes to the determination of reward threshold in humans and animals. Food restriction increases the sensitivity to drugs of abuse, while over-nutrition decreases the sensitivity to drugs. However, it is still elusive how the brain circuitry regulating the metabolic status interacts with the reward circuitry. The lateral hypothalamus (LH), a central hub integrating a wide range of inputs from various brain regions encoding metabolic, behavioral and environmental cues, is a critical brain area to regulate both energy homeostasis and food/drug reward. Specifically, a selective group of neurons exclusively synthesizing the neuropeptide hypocretin (Hcrt, also called orexin) affect food intake and play a prominent role in food award and drug addiction. It is not entirely clear what role the Hcrt system plays in the hierarchy of circuitry responsible for food reward and drug addiction. Recent studies by others and us indicate that the Hcrt system undergoes experience-dependent synaptic plasticity in animals exposed to cocaine, which leads to our overall hypothesis that the expression of experience-dependent synaptic plasticity in Hcrt cells contributes to the development of addictive behaviors in animals. If this is true, the ability to establish synaptic plasticity in Hcrt neurons may contribute to the susceptibility of animals to addictive behaviors. Based on our previous studies, we hypothesize that metabolic/energy status may determine the sensitivity to reward reinforcers through modulating activity and plasticity in Hcrt neurons in animals. In this application stemmed from an R21 grant, we will begin to address this hypothesis by determining whether either over- nutrition or chronic energy deficiency alters the ability of cocaine to trigger plasticity in the Hcrt system with molecular (Hcrt-IRES-Cre mice and DREADDs), cellular (electrophysiological and EM studies) and behavioral (cocaine conditioned place preference) approaches. Three specific aims are: 1) To determine whether over-nutrition causes adaptive changes in Hcrt neurons, which is required in the impairment of drug- seeking behaviors in animals. 2) To test whether chronic energy deficiency leads to adaptation in Hcrt neurons, which facilitates the expression of drug reward in animals. 3) To interrogate whether over-nutrition and energy deficiency-induced adaptations in Hcrt neurons lead to altered responses of target areas of the Hcrt system when animals exposed to cocaine. Our long-term goal is to bridge the knowledge gap in our current understanding of addiction and to bridge the gap between clinical studies and basic research on the role of the Hcrt system in addictive behaviors, an area of study that has not been well explored thus far.