Hypocretinergic control of cocaine abuse

可卡因滥用的低促泌素控制

基本信息

批准号：
10442500
负责人：
XIAO-BING GAO
金额：
$ 48.25万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10442500
关键词：
Acute Addictive Behavior Address Affect American Animals Area Attenuated Award Basic Science Behavior Behavioral Brain Brain region CCR Caloric Restriction Cells Chronic Chronic Disease Clinical Clinical Research Cocaine Cocaine Abuse Cocaine Dependence Country Cues Data Development Disease Drug Addiction Eating Electrophysiology (science)Energy Supply Energy-Generating Resources Exhibits Food Future Goals Grant Healthcare Systems High Fat Diet Homeostasis Human Hypothalamic structure Illicit Drugs Impairment Internal Ribosome Entry Site Knowledge Lateral Lead Malnutrition Mediating Metabolic Modeling Molecular Mus Neurons Neuropeptides Neurotransmitter Receptor Organism Overnutrition Pharmaceutical Preparations Play Predisposition Protocols documentation Regulation Rewards Risk Factors Role Signal Transduction Societies Stress Synaptic plasticity System Testing acute stress addiction base brain circuitry cell type cocaine exposure cocaine relapse conditioned place preference depressive symptoms design designer receptors exclusively activated by designer drugs diet-induced obesity dopaminergic neuron dosage drug of abuse drug reward drug seeking behavior experience food restriction hypocretin interdisciplinary approach metabolic phenotype neural circuit prevent receptor reinforcer response reward circuitry stem trait

项目摘要

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.

吸毒成瘾被认为是一种慢性疾病，也是许多其他疾病和疾病的危险因素。失调。为了更好地治疗成瘾并防止未来滥用非法药物，有必要了解成瘾行为的潜在机制。临床和动物研究已证实代谢状态有助于确定人类和动物的奖励阈值。食物限制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。然而，它调节代谢状态的大脑回路如何与奖励回路相互作用仍然难以捉摸。这下丘脑外侧 (LH)，整合来自不同大脑区域的广泛输入的中枢编码代谢、行为和环境线索，是调节能量的关键大脑区域体内平衡和食物/药物奖励。具体来说，一组选择性的神经元专门合成神经肽下丘脑分泌素（Hcrt，也称为食欲素）影响食物摄入并在食物奖励中发挥突出作用和毒瘾。目前尚不完全清楚 Hcrt 系统在电路层次结构中扮演什么角色负责食物奖励和药物成瘾。其他人和我们最近的研究表明，Hcrt 在接触可卡因的动物中，系统经历依赖于经验的突触可塑性，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，则有能力建立 Hcrt 神经元的突触可塑性可能导致动物对成瘾行为的易感性。根据我们之前的研究，我们假设代谢/能量状态可能决定对通过调节动物 Hcrt 神经元的活动和可塑性来奖励强化物。在这个应用程序中源于 R21 资助，我们将开始通过确定是否过度来解决这个假设营养或慢性能量缺乏会改变可卡因触发 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（可卡因条件位置偏好）方法。三个具体目标是： 1) 确定营养过剩是否会导致 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会导致 Hcrt 适应神经元，促进动物药物奖励的表达。 3）询问是否营养过剩 Hcrt 神经元中能量缺乏引起的适应导致目标区域的反应改变当动物接触可卡因时的 Hcrt 系统。我们的长期目标是弥合我们的知识差距当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，这是一个迄今为止尚未得到充分探索的研究领域。