The Effects of Naltrexone on Neural Responses to Methamphetamine Cues

描述(由申请人提供)：甲基苯丙胺使用障碍是一个重大且代价高昂的公共卫生问题，但治疗甲基苯丙胺依赖的有效药物疗法仍然难以找到。纳曲酮是FDA批准的一种阿片受体拮抗剂，与Mu受体的亲和力最强，kappa和Delta受体的亲和力较小，但意义不大，它代表着一种治疗甲基苯丙胺依赖的潜在有效药物。临床前和临床数据表明，纳曲酮在减少苯丙胺渴求方面是有效的；然而，这种效果背后的神经机制仍不清楚。此外，编码u-阿片受体的个人OPRM1基因可能起到缓和纳曲酮对甲基苯丙胺诱导的渴求的影响的作用。建议的NRSA应用的总体目标是通过研究纳曲酮对患者的神经生物学影响，促进我作为临床神经学家的发展。 具有和不具有OPRM1基因Asp40变异的甲基苯丙胺依赖者的甲基苯丙胺提示。为此，15名甲基苯丙胺依赖者将接受前瞻性的基因分型，并接受功能磁共振成像方案，其中提供可视甲基苯丙胺和对照线索。参与者将接受两次扫描，一次是服用目标剂量的纳曲酮(50毫克)，另一次是服用安慰剂。来自这15名参与者的数据将与我的赞助人(n=15)在正在进行的R21中获得的数据相结合，以进行最终的30名甲基苯丙胺依赖者的样本。全脑对比分析将确定与甲基苯丙胺渴望相关的激活区域，而功能连通性分析将寻求发现线索诱导渴望的启动途径。OPRM1基因以及kappa和Delta阿片受体多态将被测试为纳曲酮与安慰剂的神经成像反应的调节因子。此外，所有分析都将使用动脉自旋标记(ASL)控制药物改变的脑血流。这一转化项目的结果将通过评估甲基苯丙胺依赖的形成途径和测试纳曲酮是否有效地针对这些神经途径来促进甲基苯丙胺依赖的药物开发。

DESCRIPTION (provided by applicant): Methamphetamine use disorders represent a significant and costly public health concern, yet efficacious pharmacotherapies for methamphetamine dependence remain elusive. Naltrexone, an FDA-approved opioid receptor antagonist with greatest affinity for the mu receptor, and to a lesser but meaningful extent kappa and delta receptors, represents a potentially efficacious medication for the treatment of methamphetamine dependence. Preclinical and clinical data suggest naltrexone is effective at reducing amphetamine craving; however, the neural mechanisms underlying this effect remain unknown. Furthermore, an individual's OPRM1 genotype, which encodes the mu-opioid receptor, may function to moderate naltrexone's effect on methamphetamine cue-induced craving. The overall objective of the proposed NRSA application is to foster my development as a clinical neuroscientist through the investigation of the neurobiological effects of naltrexone on methamphetamine cues in methamphetamine dependent individuals with and without the Asp40 variant of the OPRM1 gene. To do so, 15 individuals with methamphetamine dependence will be prospectively genotyped and undergo an fMRI protocol in which visual methamphetamine and control cues are presented. The participants will be scanned twice, once while on the target dose of naltrexone (50mg) and once on placebo. The data from these 15 participants will be combined with data acquired in an ongoing R21 by my sponsor (n = 15) for a final a sample of 30 methamphetamine dependent individuals. Whole-brain contrast analyses will identify the regions of activation associated with methamphetamine craving, while functional connectivity analyses will seek to discover pathways by which cue-induced craving is instated. OPRM1 genotype, as well as kappa and delta opioid receptor polymorphisms will be tested as moderators of neuroimaging response to naltrexone versus placebo. In addition, all analyses will control for medication altered cerebral blood flow using arterial spin labeling (ASL). The results of this translational project will advance medication development for methamphetamine dependence by assessing the pathways by which methamphetamine craving is instated and by testing whether naltrexone effectively targets these neural pathways.