Pharmacogenetics of Natlrexone for Methamphetamine Use Disorder

纳曲酮治疗甲基苯丙胺使用障碍的药物遗传学

• 批准号: 8471454
• 负责人: LARA A. RAY
• 金额: $ 2.94万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8471454
• 关键词: Abstinence; Alcohols; Alleles; Amphetamine Dependence; Amphetamines; Attenuated; Binding; Candidate Disease Gene; Clinical; Clinical Treatment; Cues; Data; Disease; Dose; Double-Blind Method; Enrollment; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Haplotypes; Human; Individual; Individual Differences; Laboratories; Literature; Measures; Methamphetamine; Methamphetamine dependence; Naltrexone; Neurobiology; Opioid; Opioid Receptor; Participant; Pharmaceutical Preparations; Pharmacogenetics; Pharmacological Treatment; Pharmacotherapy; Placebos; Receptor Gene; Recruitment Activity; Research; Research Personnel; Rewards; Rodent Model; Sampling; Testing; Translating; United States; Urine; Variant; Work; addiction; alcohol effect; alcoholism therapy; base; behavioral pharmacology; behavioral sensitization; biobehavior; craving; delta opioid receptor; improved; kappa opioid receptors; meetings; mu opioid receptors; neurobiological mechanism; pharmacogenetic testing; placebo controlled study; pre-clinical; prospective; receptor; response; treatment effect; treatment response

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.

描述（由申请人提供）：在过去的十年中，甲基苯丙胺（MA）滥用在美国急剧增加。然而，尽管对苯丙胺作用的神经生物学进行了广泛的研究，但有效的MA依赖性药物治疗仍然难以捉摸。纳曲酮（NTX）是一种阿片类受体拮抗剂，具有经验支持的功效和FDA批准用于治疗酒精中毒。一项最新的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品测量的戒酒显着提高，NTX可能有望治疗苯丙胺依赖性。这位新的研究者R21试图（a）检查NTX对MA使用障碍的作用的生物行为机制； （b）测试这些疾病的NTX的药物遗传学。我们建议招募50种非待遇寻求符合MA依赖标准的个人。参与者将完成两次双眼内部的MA管理实验室会议，一次服用NTX（50 mg/天），而安慰剂进行四天后进行。假设NTX会钝化MA引起的奖励和渴望，并会改善抑制作用。此外，我们假设MU，Kappa和Delta阿片类药物受体的遗传多态性将有助于识别对NTX的响应者以及MA诱导的奖励中的个体差异。该应用程序的成功完成将提供NTX及其药物遗传学中NTX作用机理的初步表征。这项研究的长期目的是通过结合行为药理学和药物遗传学来开发和优化MA依赖性药物的药物治疗，以阐明NTX对MA使用障碍及其遗传基础的作用机制。