Mechanisms of Alcohol Reward in a Humanized OPRM1 Mouse Model

描述(申请人提供)：在美国，酒精滥用是一个主要的公共健康负担，但很少有药物疗法被批准用于治疗这种疾病。非选择性阿片受体拮抗剂纳曲酮在临床试验中是有效的，因为它似乎可以阻断 内源性阿片类药物对乙醇诱发的脑奖赏通路的激活作用。最近的证据表明，MU-阿片受体基因(OPRM1)外显子1的A118G多态性是一个与酒精滥用和依赖相关的临床相关危险因素。携带G等位基因似乎增加了患酒精使用障碍的风险，并在临床试验中预测了对阿片类药物拮抗的治疗反应，尽管这种影响的病因尚不清楚。这项建议概述了行为药理学实验，这些实验将使用A118G多态的人源化小鼠模型来确定与118A等位基因纯合子(h/m118AA)相比，118G等位基因纯合子(h/m118GG)小鼠对酒精奖励效应的敏感性是否不同。还提出了一些实验，以确定h/m118GG和h/m118AA小鼠的酒精奖赏对纳曲酮拮抗的敏感性是否存在差异。在酒精奖赏的关键部位，将在h/m118AA和h/m118GG小鼠之间比较阿片类药物的体外药理作用，以确定阿片类药物突触效应的差异是否可以解释体内行为的差异。颅内自我刺激(ICSS)是一种可操作性的行为学方法，将用于确定酒精、吗啡和可卡因的奖赏效应，并测量纳曲酮和kappa阿片受体激动剂U69,593的奖赏贬值效应。腹侧被盖区的阿片信号是脑奖励系统中阿片类药物活动的主要靶点，将用全细胞膜片钳电生理学来表征。如果得到资助，这些研究将解决A118G多态如何改变酒精的奖赏效应的重要悬而未决的问题，并增加对这种基因变异增加酗酒风险的机制的理解。拟议的培训计划将提供坚实的教育和专业基础，在此基础上从事成瘾医学领域的内科科学家职业生涯。

DESCRIPTION (provided by applicant): Alcohol abuse is a major public health burden in the United States, yet few pharmacotherapies are approved to treat this disease. Naltrexone, a non-selective opioid receptor antagonist, has been effective in clinical trials, as it appears to block the ethanol-evoked activation of brain reward pathways by endogenous opioids. Recent evidence suggests that the A118G polymorphism in exon 1 of the mu-opioid receptor gene (OPRM1) is a clinically relevant risk factor associated with alcohol abuse and dependence. Carrying the G- allele appears to increase the risk of developing alcohol use disorders and predicts treatment response to opioid antagonism in clinical trials, although the etiology of this effect is unclear. This proposal outlines behavioral pharmacology experiments that will employ a humanized mouse model of the A118G polymorphism to determine if sensitivity to the rewarding effects of alcohol is different in mice homozygous for the 118G-allele (h/m118GG) compared to those homozygous for the 118A-allele (h/m118AA). Experiments are also proposed that will determine if the sensitivity of alcohol reward to antagonism by naltrexone differs between h/m118GG and h/m118AA mice. Pharmacological effects of opioids in vitro will be compared between h/m118AA and h/m118GG mice in a site that is critical to alcohol reward to determine if differences in the synaptic effects of opioids may explain behavioral differences in vivo. Intracranial self-stimulation (ICSS), an operant behavioral method, will be used to determine the rewarding effects of alcohol, morphine, and cocaine and to measure the reward-devaluing effects of naltrexone and a kappa-opioid receptor agonist, U69,593. Opioid signaling in the ventral tegmental area, a major target of opioid activity in the brain reward system, will be characterized with whole-cell patch clamp electrophysiology. If funded, these studies will address important unanswered questions about how the A118G polymorphism alters the rewarding effects of alcohol and increase understanding of the mechanism through which this genetic variant increases risk for alcohol abuse. The proposed training plan will provide a solid educational and professional foundation on which to pursue a career as a physician-scientist in the field of addiction medicine.