Mechanisms of Alcohol Reward in a Humanized OPRM1 Mouse Model

人源化 OPRM1 小鼠模型中的酒精奖励机制

基本信息

批准号：
8315286
负责人：
John Elliott Robinson
金额：
$ 3.17万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8315286
关键词：
Acute Address Affect Agonist Alcohol abuse Alcohol consumption Alcohol dependence Alcohols Alleles Attenuated Behavioral Biological Brain Cells Clinical Trials Cocaine Data Disease Disinhibition Dopamine Electric Stimulation Electrophysiology (science)Ethanol Etiology Exons Foundations Funding Genetic Genetic Polymorphism Genetic Variation Genotype Homozygote Human Hypothalamic structure In Vitro Interneurons Lateral Measures Mediating Medicine Methods Midbrain structure Missense Mutation Morphine Motivation Mus Mutation Naltrexone Narcotic Antagonists Neurons Opioid Opioid Receptor Pathway interactions Peptides Pharmaceutical Preparations Pharmacogenetics Pharmacotherapy Physicians Physiologic pulse Physiological Positioning Attribute Probability Property Public Health Receptor Gene Research Rewards Risk Risk Factors Scientist Self Stimulation Signal Transduction Single Nucleotide Polymorphism Site Slice Solid Stimulus Synapses System Testing Therapeutic Training Transgenic Mice Translating United States Ventral Tegmental Area addiction alcohol effect alcohol reward alcohol use disorder base behavior measurement behavioral pharmacology career clinically relevant dopaminergic neuron drinking drug of abuse endogenous opioids experience gamma-Aminobutyric Acid genetic variant in vivo inhibitor/antagonist kappa opioid receptors median forebrain bundle motivated behavior mouse model mu opioid receptors neurotransmission patch clamp postsynaptic research study response reward circuitry therapeutic target treatment response

项目摘要

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. PUBLIC HEALTH RELEVANCE: Alcohol use disorders, which have a strong genetic component, are a major public health burden in the United States. I propose using a humanized mouse model of the clinically-relevant A118G polymorphism in the human mu-opioid receptor gene to investigate pharmacogenetic mechanisms of alcohol reward. These studies may identify cellular mechanisms by which this polymorphism increases the probability of alcohol abuse and predicts therapeutic response to mu-opioid receptor antagonists.

描述（由申请人提供）：酒精滥用是美国的一个主要公共卫生负担，但很少有药物疗法被批准用于治疗这种疾病。纳曲酮是一种非选择性阿片受体拮抗剂，在临床试验中已有效，因为它似乎可以阻断乙醇诱发内源性阿片类药物激活大脑奖赏通路。最近的证据表明，mu-阿片受体基因 (OPRM1) 外显子 1 中的 A118G 多态性是与酒精滥用和依赖相关的临床相关危险因素。携带G等位基因似乎会增加患酒精使用障碍的风险，并在临床试验中预测对阿片类药物拮抗剂的治疗反应，尽管这种效应的病因尚不清楚。该提案概述了行为药理学实验，该实验将采用 A118G 多态性的人源化小鼠模型来确定 118G 等位基因 (h/m118GG) 纯合子小鼠与 118A- 等位基因纯合子小鼠对酒精奖赏效应的敏感性是否不同。等位基因 (h/m118AA)。还提出了实验来确定 h/m118GG 和 h/m118AA 小鼠之间酒精奖赏对纳曲酮拮抗作用的敏感性是否不同。将在对酒精奖励至关重要的位点比较 h/m118AA 和 h/m118GG 小鼠之间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差异。颅内自我刺激 (ICSS) 是一种操作行为方法，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传导是大脑奖励系统中阿片类药物活性的主要目标，将通过全细胞膜片钳电生理学来表征。如果获得资助，这些研究将解决有关 A118G 多态性如何改变酒精的奖励效应的重要未解答问题，并增进对这种遗传变异增加酗酒风险的机制的理解。拟议的培训计划将为成瘾医学领域的医师科学家职业生涯提供坚实的教育和专业基础。公共卫生相关性：酒精使用障碍具有很强的遗传因素，是美国的主要公共卫生负担。我建议使用人类 mu-阿片受体基因中临床相关 A118G 多态性的人源化小鼠模型来研究酒精奖赏的药物遗传学机制。这些研究可能会确定这种多态性增加酗酒可能性的细胞机制，并预测对 mu-阿片受体拮抗剂的治疗反应。