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：
7729548
负责人：
Donna M Platt
金额：
$ 41.21万
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/7729548
关键词：
Affect Alcohol abuse Alcohol consumption Alcohol dependence Alcoholism Alcohols Arts Behavioral Code Dependence Effectiveness Gene Expression Genetic Genetic Polymorphism Genetic Variation Genotype Haplotypes Human In Vitro Individual Individual Differences Macaca mulatta Maintenance Medical Modeling Naltrexone Narcotic Antagonists 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 public health relevance 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）：酗酒和酗酒是普遍存在的公共卫生问题，与令人衰弱的医疗、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，纳曲酮并非对所有人都普遍有效。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) 可能导致对酒精行为影响的敏感性的个体差异，以及随后对纳曲酮治疗的反应。恒河猴也有一个 SNP（P26R、C77G），它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测定，将系统地鉴定和表征恒河猴 mu 阿片受体的等位基因变体，这些变体改变蛋白质结构和/或功能或影响后续基因表达水平（具体目标 1）。此外，还将在恒河猴中探索 mu 阿片受体单倍型在个体对酒精的增强和复发诱导作用的敏感性中的作用，这些恒河猴是根据其 mu 阿片受体 P26R 基因型先验选择的，并经过训练自行口服酒精（具体目标 2）。最后，将在根据 mu 阿片类药物先验选择的恒河猴中研究 mu 阿片类药物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的恢复能力的反应中的作用。受体 P26R 基因型，并接受过口服自我饮酒训练（具体目标 3）。整合这三个具体目标的结果将产生所需的信息，了解特定的遗传变量如何在酒精成瘾影响的脆弱性中发挥作用。最终，结果应该允许根据个人获得积极治疗结果的可能性来更明智地选择抗酒精药物。公共卫生相关性：酒精使用障碍是普遍存在的公共卫生问题，与令人衰弱的医疗、社会和心理后果有关，并且没有普遍有效的治疗药物。我们的研究将提供有关特定遗传变量如何在酒精成瘾影响中发挥作用的关键信息。最终，我们的结果应该允许根据个人积极治疗反应的可能性来更明智地选择抗酒精药物。