Mechanisms of Alcohol Reward in a Humanized OPRM1 Mouse Model

描述（由申请人提供）：酒精滥用是美国主要的公共卫生负担，但很少有药物治疗被批准用于治疗这种疾病。纳洛酮是一种非选择性阿片受体拮抗剂，在临床试验中是有效的，因为它似乎可以阻断 乙醇诱发的内源性阿片类物质激活大脑奖赏通路。最近的证据表明，μ阿片受体基因（OPRM 1）外显子1中的A118 G多态性是与酒精滥用和依赖相关的临床相关风险因素。携带G等位基因似乎增加了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作用的治疗反应，尽管这种作用的病因尚不清楚。该提案概述了行为药理学实验，该实验将采用A118 G多态性的人源化小鼠模型，以确定与118 A等位基因纯合子小鼠（h/m118 AA）相比，118 G等位基因纯合子小鼠（h/m118 GG）对酒精奖励效应的敏感性是否不同。实验还提出，将确定酒精奖励的敏感性，以拮抗纳洛酮之间的h/m118 GG和h/m118 AA小鼠不同。将在h/m118 AA和h/m118 GG小鼠之间比较阿片类药物的体外药理学作用，该部位对酒精奖励至关重要，以确定阿片类药物的突触作用差异是否可以解释体内行为差异。颅内自我刺激（ICSS）是一种操作性行为方法，将用于确定酒精、吗啡和可卡因的奖励效应，并测量纳洛酮和κ阿片受体激动剂U69，593的奖励贬值效应。腹侧被盖区的阿片样物质信号传导是脑奖赏系统中阿片样物质活性的主要靶点，将用全细胞膜片钳电生理学表征。如果获得资助，这些研究将解决关于A118 G多态性如何改变酒精的奖励效应的重要未回答的问题，并增加对这种遗传变异增加酒精滥用风险的机制的理解。拟议的培训计划将提供一个坚实的教育和专业基础，在此基础上追求职业生涯作为一个医生，科学家在成瘾医学领域。

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.