Using Pharmacogenetics to Better Evaluate Naltrexone for Treating Stimulant Abuse

 描述（由申请人提供） 据认为，全世界有超过7500万人滥用安非他明和可卡因。与海洛因、酒精或尼古丁等药物不同，没有FDA批准的药物来促进精神兴奋剂滥用的治疗。几项临床前和临床研究提供的数据表明，纳洛酮（NTX）可能具有这种适应症的潜力。然而，对文献的回顾揭示了需要解决的相互矛盾的发现。几项临床研究表明，遗传变异缓和了许多用于治疗物质使用障碍的药物的效果。最近的一项荟萃分析得出结论，OPRM 1 A118 G SNP（rs 1799971）显著调节NTX治疗酒精滥用的疗效，使G等位基因携带者（AG/GG）的疗效提高2倍以上。拟议的应用将是第一个调查这种基因型在NTX治疗兴奋剂滥用的疗效中的调节作用。更具体地说，我们建议研究NTX和鼻内（IN）甲基苯丙胺（50 mg/70 kg）之间的相互作用。符合DSM-V标准的中度至重度兴奋剂使用障碍的参与者将完成测试，其中在NTX（0，25，50 mg）预处理后评估IN甲基苯丙胺（M-AMPH）的滥用倾向。纳洛酮对IN M-AMPH滥用可能性的影响将使用积极主观效应和药物自我给药的自我报告测量进行评估。将在A118 G A等位基因纯合子（AA）和G等位基因携带者（AG/GG;预计占总样本的25%）之间比较药物对这些经验证的滥用预测因子的影响，以评估治疗结局的遗传调节作用。这种方法的优点是，它可能有助于确定治疗发挥最大作用的个体。作为研究的次要目的，我们将同时评估几种功能相关遗传变异的可能调节作用，以预测 NTX如何改变IN M-AMPH [ANKK 1（rs 1800497）; DβH（rs 1611115）; DRD 2（rs 2283265）; OPRM 1（rs6912029）; SLC 6A 3（rs 28363170）]的主观和强化效应。因此，本研究采用了一种集中的方法来评估遗传多态性的影响，其影响已被其他研究证实，并采用探索性方法来评估几个可能的遗传调节因子的个体和综合影响。结合起来，本提案中的两项研究将有助于评估NTX fr治疗精神兴奋剂滥用的临床效用，并可能有助于确定有助于个性化治疗的基因x药理学相互作用。

 DESCRIPTION (provided by applicant) There is thought to be over 75 million abusers of amphetamines (AMPHs) and cocaine worldwide. Unlike drugs such as heroin, alcohol or nicotine, there is no FDA-approved medication to facilitate the treatment of psychostimulant abuse. Several preclinical and clinical studies have provided data suggesting that naltrexone (NTX) may have potential for this indication. However, a review of the literature reveals conflicting findings that require resolutio. Several clinical studies have shown that genetic variation moderates the effects of a number of medications used to treat substance use disorders. A recent meta-analysis concluded that the OPRM1 A118G SNP (rs1799971) significantly moderates the treatment efficacy of NTX in treating alcohol abuse, increasing the treatment efficacy by over 2 fold among G-allele carriers (AG/GG). The proposed application would be the first to investigate the moderating effect of this genotype in the efficacy of NTX to treat stimulant abuse. More specifically, we propose investigating the interaction between NTX and intranasal (IN) methamphetamine (50mg/70kg). Participants who meet DSM-V criteria for moderate-to-severe stimulant use disorder will complete testing sessions where the abuse liability of IN methamphetamine (M-AMPH) is assessed following pretreatment with NTX (0, 25, 50 mg). Naltrexone's effects upon the abuse potential of IN M-AMPH will be assessed using self-report measurements of positive subjective effects and drug self- administration. Medication effects on these validated predictors of abuse will be compared between A118G A allele homozygotes (AA) and G-allele carriers (AG/GG; an anticipated 25% of the total sample), in order to assess genetic moderation of treatment outcome. The advantage of this approach is that it may help to define individuals in which the treatment exerts its greatest effects. As a secondary aim of the study we will simultaneously assess for possible moderating effects of several functionally relevant genetic variants to predict the how NTX alters the subjective and reinforcing effects of IN M-AMPH [ANKK1 (rs1800497); DβH (rs1611115); DRD2 (rs2283265); OPRM1 (rs6912029); SLC6A3 (rs28363170)]. This study therefore utilizes a focused approach to assess the influence of a genetic polymorphism whose influence has been substantiated by other investigations, and an exploratory approach to assess the individual and combined influence of several likely genetic moderators. Combined, the two studies in this proposal will contribute to the assessment of the clinical utility of NTX fr treating psychostimulant abuse, and may help identify gene x pharmacological interactions contributing to the personalization of treatment.