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

• 批准号: 8617202
• 负责人: John Elliott Robinson
• 金额: $ 3.22万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/8617202
• 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; median forebrain bundle; motivated behavior; mouse model; mu opioid receptors; neurotransmission; patch clamp; postsynaptic; research study; response; reward circuitry; therapeutic target; treatment response; 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; median forebrain bundle; motivated behavior; mouse model; mu opioid receptors; neurotransmission; patch clamp; postsynaptic; research study; response; reward circuitry; therapeutic target; treatment response

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.

描述（由申请人提供）：酗酒是美国的主要公共卫生负担，但很少有药物治疗来治疗这种疾病。纳曲酮是一种非选择性阿片类药物拮抗剂，在临床试验中已有效，因为它似乎阻止了 乙醇诱发的脑奖励途径通过内源性阿片类药物奖励途径。最近的证据表明，MU-阿片受体基因（OPRM1）的外显子1中的A118G多态性是与酒精滥用和依赖性相关的临床危险因素。携带G-等位基因似乎会增加患饮酒障碍的风险，并在临床试验中预测治疗对阿片类药物拮抗作用的反应，尽管这种作用的病因尚不清楚。该提案概述了将采用A118G多态性的人源化小鼠模型的行为药理学实验，以确定与118G或118G（H/M118GG）纯合的小鼠中对酒精奖励作用的敏感性是否有所不同。还提出了实验，该实验将确定纳曲酮与H/M118GG和H/M118AA小鼠之间对酒精对拮抗作用的敏感性是否不同。在对酒精奖励至关重要的位点中，将比较阿片类药物在体外的药理作用，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（ICS）是一种操作行为方法，将用于确定酒精，吗啡和可卡因的奖励作用，并测量纳曲酮和Kappa-阿片类受体激动剂的奖励评估效果U69,593，U69,593。腹侧对段区域的阿片类药物信号传导是大脑奖励系统中阿片类药物活性的主要目标，将以全细胞贴片夹电生理学为特征。如果资助，这些研究将解决有关A118G多态性如何改变酒精的有意义影响并增加对这种遗传变异增加酒精滥用风险的机制的理解的重要问题。拟议的培训计划将为成瘾医学领域的医师科学家从事稳固的教育和专业基础。