Pharmacogenetics of Natlrexone for Methamphetamine Use Disorder

描述（由申请人提供）：在过去十年中，甲基苯丙胺（MA）的滥用在美国急剧增加。然而，尽管对安非他明的神经生物学作用进行了广泛的研究，但对MA依赖的有效药物治疗仍然难以捉摸。纳曲酮（NTX）是一种阿片受体拮抗剂，具有经验支持的疗效和fda批准用于治疗酒精中毒。最近的一项安慰剂对照研究表明，与安慰剂相比，通过苯丙胺阴性尿液样本测量，NTX可能有望治疗苯丙胺依赖，因为它显着增加了戒断。新研究者R21寻求(a)检查NTX治疗MA使用障碍的生物行为机制；(b)测试NTX治疗这些疾病的药物遗传学。我们建议招募50名符合MA依赖标准的非寻求治疗的个体。参与者将完成两次双盲的MA给药实验，一次是在服用NTX（50毫克/天）后，另一次是在服用安慰剂四天后。假设NTX会减弱ma诱导的奖励和渴望，并改善反应抑制。此外，我们假设mu， kappa和delta阿片受体的遗传多态性将有助于识别NTX应答者和ma诱导奖励的个体差异。该应用程序的成功完成将提供nttx在MA滥用者中的作用机制及其药物遗传学的初步表征。本研究的长期目标是结合行为药理学和药物遗传学，开发和优化MA依赖的药物治疗方法，阐明NTX治疗MA使用障碍的作用机制及其遗传基础。

DESCRIPTION (provided by applicant): Methamphetamine (MA) misuse has increased dramatically in the United States during the past decade. Nevertheless, efficacious pharmacotherapies for MA dependence remain elusive despite extensive research on the neurobiology of the effects of amphetamines. Naltrexone (NTX) is an opioid receptor antagonist with empirically supported efficacy and FDA-approval for the treatment of alcoholism. A recent placebo-controlled study has suggested that NTX may be promising for the treatment of amphetamine dependence as it significantly increased abstinence, measured by amphetamine-negative urine samples, compared to placebo. This New Investigator R21 seeks to (a) examine the biobehavioral mechanisms of action of NTX for MA use disorders; and (b) test the pharmacogenetics of NTX for these disorders. We propose to recruit 50 non- treatment seeking individuals who meet criteria for MA dependence. Participant will complete two double- blinded, within-subjects MA administration laboratory sessions, one after taking NTX (50 mg/day) and one after taking placebo for four days. It is hypothesized that NTX will blunt MA-induced reward and craving and will improve response inhibition. In addition, we hypothesize that genetic polymorphisms of the mu, kappa, and delta opioid receptors will be useful in identifying responders to NTX and individual differences in MA-induced reward. The successful completion of this application will provide an initial characterization of the mechanisms of action of NTX among MA abusers and its pharmacogenetics. The long-term objective of this research is to develop and optimize pharmacotherapies for MA dependence by combining behavioral pharmacology and pharmacogenetics to elucidate the mechanisms of action of NTX for MA use disorders and their genetic bases.