Opioid Receptor Polymorphisms and Nonhuman Primate Models of Alcohol Abuse

描述（由申请人提供）：酒精滥用和酒精中毒是广泛的公共卫生问题，与衰弱的医疗，社会和心理后果有关。阿片类拮抗剂纳洛酮被批准用于治疗酒精依赖;然而，纳洛酮并不是对所有人都有效。最近的证据表明，人类μ阿片受体基因中的N40 D（A188 G）单核苷酸多态性（SNP）可能有助于个体对酒精行为影响的敏感性变化，以及随后对纳洛酮治疗的反应性。恒河猴也有一个SNP（P26 R，C77 G），似乎具有许多与人类SNP相同的功能，生理和行为后果。使用最先进的基因分型技术和体外试验，将系统地鉴定和表征改变蛋白质结构和/或功能或影响后续基因表达水平的恒河猴μ阿片受体的等位基因变体（特定目的1）。此外，将在恒河猴中探索μ阿片受体单倍型在个体对酒精的强化和复发诱导作用的敏感性中的作用，所述恒河猴已根据其μ阿片受体P26 R基因型进行先验选择，并已接受口服自我给药酒精的训练（具体目标2）。最后，将在恒河猴中研究μ阿片样物质受体单倍型在对纳洛酮减少口服酒精自我给药和减少酒精引发诱导的恢复的能力的个体响应性中的作用，所述恒河猴已经基于其μ阿片样物质受体P26 R基因型被先验选择并且已经被训练为口服自我给药酒精（具体目标3）。整合三个具体目标的结果将产生所需的信息，具体的遗传变量如何在酒精成瘾效应的脆弱性中发挥作用。最终，这些结果应该允许更明智地选择针对个人积极治疗结果可能性的抗酒精药物。

DESCRIPTION (provided by applicant): Alcohol abuse and alcoholism are widespread public health problems that are associated with debilitating medical, social, and psychological consequences. The opioid antagonist naltrexone is approved for the treatment of alcohol dependence; however, naltrexone is not universally effective in all people. Recent evidence suggests that a N40D (A188G) single nucleotide polymorphism (SNP) in the human mu opioid receptor gene may contribute to individual variation in sensitivity to the behavioral effects of alcohol, as well as to subsequent responsiveness to naltrexone therapy. Rhesus monkeys also have a SNP (P26R, C77G) that appears to have many of the same functional, physiological and behavioral consequences as the human SNP. Using state-of-the-art genotyping techniques and in vitro assays, allelic variants of the rhesus monkey mu opioid receptor that alter protein structure and/or function or affect subsequent gene expression levels will be systematically identified and characterized (Specific Aim 1). In addition, the role of mu opioid receptor haplotypes in individual sensitivity to the reinforcing and relapse-inducing effects of alcohol will be explored in rhesus monkeys that have been selected a priori on the basis of their mu opioid receptor P26R genotype and have been trained to orally self-administer alcohol (Specific Aim 2). Finally, the role of mu opioid receptor haplotypes in individual responsiveness to the ability of naltrexone to reduce oral alcohol self-administration and diminish alcohol priming-induced reinstatement will be investigated in rhesus monkeys that have been selected a priori on the basis of their mu opioid receptor P26R genotype and have been trained to orally self- administer alcohol (Specific Aim 3). Integration of results from the three specific aims will yield needed information about how specific genetic variables may play a role in vulnerability to the addictive effects of alcohol. Ultimately, the results should allow for a more informed selection of anti-alcohol medication that is tailored to an individual's likelihood of positive treatment outcome.