Evaluating the Genetic Variability of Naltrexone Response

纳洛酮减少了一些但不是所有酗酒者的渴望和复发。一个潜在的变量， 可能预测纳洛酮，并可能其他阿片拮抗剂的反应，是一个单一的差异， μ阿片受体蛋白中的核苷酸取代，使该受体对 内源性β-内啡肽以及外源性阿片拮抗剂如纳洛酮。（A）denine to （G）μ阿片受体编码区118位（A118 G）的鸟嘌呤取代导致了 受体中40位的天冬酰胺（asn）氨基酸取代为天冬氨酸（asp）（asn 40 asp） 这种蛋白质存在于大约15%的人群中。本提案的目的是审查 这种等位基因的差异，纳洛酮反应在一个良好的建立亚急性剂量，脑成像， 酒吧实验室模式与另一个功能等位基因差异的相互作用（va！158 met取代）在儿茶酚-甲基- 转移酶（COMT），一种控制中枢神经系统多巴胺张力的酶，将被探索。 将对300名不寻求治疗的酗酒者进行评估，并对mu阿片受体进行亚型分析。 和COMT等位基因变体。80个个体（40个具有更常见的AA基因，40个具有AG基因）， 或GG基因）将被随机分配服用纳洛酮（50 mg/天）或匹配的安慰剂7 天COMT基因的瓦尔和Met等位基因将通过urn随机化平均分布至所有组。 在5天的自然饮酒和1天的戒酒后，受试者将经历一个酒精线索诱导的 研究药物给药第6天进行fMRI脑扫描。第7天，在标准酒精饮料、刺激、镇静后， 中毒和渴望将在40分钟内进行评估。然后受试者可以选择喝多达8个迷你饮料 在两小时内。 假设当服用纳洛酮时，AG/GG（40 asp）受试者与 AA（40 asn）将显示出更大的减少线索诱导的脑刺激在延髓核， 酒精诱导的刺激，以及较少的自由选择饮酒。同时具有asn 40 asp和val 158 met的 取代可能对纳洛酮具有最强的反应。这些数据将为使用 基因分型在预测寻求酒精治疗将或将不响应纳洛酮。而且这 这项工作为我们的中心带来了药物遗传学，用于未来的药物/基因相互作用研究。

Naltrexone has reduced craving and relapse in some, but not all, alcoholics. One potential variable that might predict naltrexone, and potentially other opiate antagonist responses, is a difference in a single nucleotide substitution in the mu opiate receptor protein that makes that receptor respond differently to endogenous beta-endorphin as well as to exogenous opiate antagonists like naltrexone. An (A)denine to (G)uanine substitution at position 118 (A118G) in the coding region of the mu opiate receptor accounts for an asparagines (asn) to aspartate (asp) amino acid substitution at position 40 (asn40asp) in the receptor protein that occurs in about 15% of the population. The purpose of this1 proposal is to examine the role of this allelic difference in naltrexone responsivity in a well-established sub-acute dosing, brain imaging, and bar-lab paradigm. Interaction with another functional allele difference (va!158met substitution) in catechol-omethyl- transferase (COMT), an enzyme that controls CNS dopamine tone, will be explored. Three hundred non-treatment seeking alcoholics will be assessed and subtyped for mu opiate receptor and COMT allelic variants. Eighty individuals (40 with the more common AA gene and 40 with either an AG or GG gene) will be randomly assigned to take either naltrexone (50 mg/day) or a matching placebo for 7 days. Val and Met alleles of the COMT gene will be equally distributed by urn randomization to all groups. After 5 days of natural drinking and one day of abstinence, subjects will undergo an alcohol cue-induced fMRI brain scan on day 6 of study drug. On day 7, after a standard alcohol drink, stimulation, sedation, intoxication, and craving will be evaluated over 40 minutes. Then subjects may choose to drink up to 8 minidrinks over a 2-hour period. It is hypothesized that when taking naltrexone, AG/GG (40asp) subjects compared to subjects with the AA (40asn) will show a greater reduction of cue-induced brain stimulation in the nucleus accumbens, less alcohol induced stimulation, and less free choice drinking. Those with both the asn40asp and val158met substitutions could have the strongest responses to naltrexone. This data will provide support for the use of genotyping in predicting which treatment seeking alcoholic will or will not respond to naltrexone. Also, this work brings pharmacogenetics to our Center for future medication/gene interaction studies.