Pharmacogenetics of Natlrexone for Methamphetamine Use Disorder

描述(申请人提供)：甲基苯丙胺(MA)滥用在过去十年中在美国急剧增加。然而，尽管对苯丙胺影响的神经生物学进行了广泛的研究，但治疗MA依赖的有效药物疗法仍然难以捉摸。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批准的治疗酒精中毒的疗效。最近的一项安慰剂对照研究表明，与安慰剂相比，NTX可能有希望用于治疗苯丙胺依赖，因为与安慰剂相比，它显著增加了苯丙胺阴性尿样的戒断率。这一新的调查者R21寻求(A)检查NTX对MA使用障碍的生物行为作用机制；以及(B)测试NTX对这些障碍的药物遗传学。我们建议招募50名符合MA依赖标准的非治疗寻求者。参与者将完成两次双盲的受试者内MA给药实验室疗程，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。据推测，NTX将钝化MA诱导的奖赏和渴求，并改善反应抑制。此外，我们假设，u、kappa和Delta阿片受体的遗传多态将有助于识别NTX的反应者和MA诱导的奖赏的个体差异。这项申请的成功完成将提供NTX在MA滥用者中的作用机制及其药物遗传学的初步特征。本研究的长期目标是通过结合行为药理学和药物遗传学来开发和优化MA依赖的药物治疗，以阐明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.