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普遍存在的公共卫生问题，与使人衰弱的医疗、社会和心理后果有关。阿片类拮抗剂纳曲酮被批准用于治疗酒精依赖；然而，纳曲酮并不是对所有人都有效。最近的证据表明，人类mu阿片受体基因中的N40D （A188G）单核苷酸多态性（SNP）可能导致个体对酒精行为影响的敏感性差异，以及随后对纳曲酮治疗的反应性差异。恒河猴也有一个SNP (P26R, C77G)，似乎具有许多与人类SNP相同的功能，生理和行为后果。利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恒河猴mu阿片受体的等位变异，这些变异会改变蛋白质结构和/或功能，或影响随后的基因表达水平（Specific Aim 1）。此外，我们还将在基于μ阿片受体P26R基因型的恒河猴中探索μ阿片受体单倍型在个体对酒精增强和诱导复发效应的敏感性中的作用，这些恒河猴已经被预先选择，并被训练为口服自我给药酒精（Specific Aim 2）。最后，我们将在恒河猴中研究mu阿片受体单倍型在个体对纳曲酮减少口服酒精自我给药和减少酒精启动诱导恢复能力的反应性中的作用，这些恒河猴是根据它们的mu阿片受体P26R基因型先验选择的，并经过口服自我给药的训练（Specific Aim 3）。将这三个具体目标的结果综合起来，就能得到所需的信息，了解特定的遗传变量如何在酒精成瘾的易感性中发挥作用。最终，研究结果应该允许更明智的选择抗酒精药物，以适应个人积极治疗结果的可能性。公共卫生相关性：酒精使用障碍是广泛存在的公共卫生问题，与使人衰弱的医疗、社会和心理后果有关，目前尚无普遍有效的治疗药物。我们的研究将提供关键信息，了解特定的遗传变量如何在酒精成瘾的易感性中发挥作用。最终，我们的结果应该允许更明智的选择抗酒精药物，以适应个人积极治疗反应的可能性。

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. PUBLIC HEALTH RELEVANCE: Alcohol use disorders are widespread public health problems that are associated with debilitating medical, social, and psychological consequences and for which no universally effective treatment medication is available. Our studies will yield key information about how specific genetic variables may play a role in vulnerability to the addictive effects of alcohol. Ultimately, our results should allow for a more informed selection of anti-alcohol medication that is tailored to an individual's likelihood of positive treatment response.