Opioid Receptor Polymorphisms and Nonhuman Primate Models of Alcohol Abuse

阿片受体多态性和酒精滥用的非人类灵长类动物模型

基本信息

批准号：
8118048
负责人：
Donna M Platt
金额：
$ 39.21万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8118048
关键词：
Affect Alcohol abuse Alcohol consumption Alcohol dependence Alcoholism Alcohols Behavioral Code Effectiveness Gene Expression Genetic Genetic Polymorphism Genetic Variation Genotype Haplotypes Health Human In Vitro Individual Individual Differences Macaca mulatta Maintenance Medical Modeling Naltrexone Narcotic Antagonists Opioid Opioid Receptor Oral Pharmaceutical Preparations Pharmacogenomics Pharmacology Pharmacotherapy Physiological Play Procedures Proteins Public Health Receptor Gene Relapse Research Role Self Administration Self-Administered Single Nucleotide Polymorphism Techniques Therapeutic Training Treatment Efficacy Treatment outcome Untranslated Regions Variant alcohol effect alcohol seeking behavior alcohol sensitivity alcohol use disorder alcoholism therapy base brain tissue effective therapy in vitro Assay mRNA Expression mu opioid receptors neurogenetics nonhuman primate novel strategies protein structure psychologic receptor response social treatment response

项目摘要

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.

描述（由申请人提供）：酗酒和酒精中毒是与医疗，社会和心理后果衰弱有关的广泛公共健康问题。阿片类拮抗剂纳曲酮被批准用于治疗酒精依赖性。但是，纳曲酮在所有人中并不普遍。最近的证据表明，人类MU阿片类受体基因中的N40D（A188G）单核苷酸多态性（SNP）可能有助于对酒精行为影响的敏感性以及随后对Naltrexone疗法的敏感性变化。恒河猴还具有SNP（P26R，C77G），似乎具有许多与人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测定，将系统地鉴定并表征恒河猴猴子Mu阿片受体的等位基因变体，以改变蛋白质结构和/或功能或影响随后的基因表达水平（特定目标1）。此外，在恒河猴中，将探索MU阿片受体单倍型在对饮酒增强和诱导饮酒诱导作用的个人敏感性中的作用，这些恒河猴会根据其MU阿片受体P26R基因型的先验选择，并已接受过口头培训，并已接受过口化的自我Administerloch酒精（特定的目标2）。最后，将在恒河猴中选择了MU阿片受体单倍型单倍型在对纳曲酮减少口服饮酒自我给药和降低酒精启动引起的恢复原状的能力的个人反应中的作用，这些猴子会根据其MU apoibiet受体P26R P56R的训练和训练有素的训练（或者是训练有素的）。来自三个特定目标的结果的整合将产生有关特定遗传变量如何在易上成瘾作用中发挥作用的所需信息。最终，结果应允许更明智的抗酒精药物选择，该药物是根据个人的阳性治疗结果量身定制的。公共卫生相关性：酒精使用障碍是与医疗，社会和心理后果衰弱的广泛公共卫生问题，并且没有普遍有效的治疗药物可用。我们的研究将产生有关特定遗传变量如何在易上成瘾作用中发挥作用的关键信息。最终，我们的结果应允许更明智的抗酒精药物选择，该药物是根据个人对阳性治疗反应的可能性量身定制的。