The Effects of Naltrexone on Neural Responses to Methamphetamine Cues

纳曲酮对甲基苯丙胺线索神经反应的影响

• 批准号: 8596761
• 负责人: Kelly Elizabeth Courtney
• 金额: $ 3.54万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596761
• 关键词: 12 year old; Admission activity; Affect; Affinity; Alcohol dependence; Amphetamine Dependence; Amphetamines; Area; Attenuated; Brain; Cerebrovascular Circulation; Clinical; Clinical Data; Clinical Sciences; Clinical Trials; Corpus striatum structure; Cues; Data; Development; Disease; Dopamine; Dose; Double-Blind Method; Educational workshop; Extinction (Psychology); FDA approved; Fostering; Functional Magnetic Resonance Imaging; Funding; Future; Genes; Genetic; Genetic Polymorphism; Genotype; Human; Individual; Intervention; Investigation; Knockout Mice; Knowledge; Link; Magnetic Resonance Imaging; Measures; Methamphetamine; Methamphetamine dependence; Methods; Mus; Naltrexone; Narcotic Antagonists; National Institute of Drug Abuse; National Research Service Awards; Neural Pathways; Neurobiology; Opioid Receptor; Outpatients; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Placebo Control; Placebos; Predoctoral Individual National Research Service Award; Process; Protocols documentation; Public Health; Role; Sampling; Scanning; Self Administration; Societies; Spin Labels; Sum; System; Testing; Therapeutic; Training; Variant; Visual; Work; addiction; behavioral pharmacology; behavioral sensitization; craving; delta opioid receptor; design; drug craving; drug seeking behavior; endogenous opioids; genetic variant; indexing; kappa opioid receptors; mesolimbic system; methamphetamine abuse; mu opioid receptors; neuroimaging; neuromechanism; novel; placebo controlled study; pre-clinical; public health relevance; receptor; relating to nervous system; response; reward processing; statistics; substance abuser

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.

描述（由申请人提供）：甲基苯丙胺使用障碍是一个重大且昂贵的公共卫生问题，但甲基苯丙胺依赖的有效药物治疗仍然难以捉摸。纳洛酮是一种FDA批准的阿片受体拮抗剂，对μ受体具有最大亲和力，对κ和δ受体具有较小但有意义的亲和力，是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，纳洛酮可有效减少安非他明的渴求;然而，这种作用的神经机制仍然未知。此外，个体的OPRM 1基因型（编码μ-阿片受体）可能起到缓和纳洛酮对甲基苯丙胺线索诱导的渴望的作用。NRSA申请的总体目标是通过研究纳洛酮的神经生物学作用，促进我作为临床神经科学家的发展。 甲基苯丙胺线索在甲基苯丙胺依赖个体与Asp 40变异的OPRM 1基因。为此，将对15名甲基苯丙胺依赖者进行前瞻性基因分型，并进行功能磁共振成像（fMRI）方案，其中提供视觉甲基苯丙胺和对照线索。受试者将接受两次扫描，一次是目标剂量的纳洛酮（50 mg），一次是安慰剂。这15名受试者的数据将与我的申办者（n = 15）在正在进行的R21中获得的数据相结合，以获得30名甲基苯丙胺依赖者的最终样本。全脑对比分析将确定与甲基苯丙胺渴望相关的激活区域，而功能连接分析将寻求发现线索诱导的渴望被启动的途径。OPRM 1基因型以及κ和δ阿片受体多态性将作为纳洛酮与安慰剂的神经影像学反应的调节剂进行检测。此外，所有分析将使用动脉自旋标记（ASL）控制药物改变的脑血流量。这个转化项目的结果将通过评估甲基苯丙胺渴望的途径和测试纳洛酮是否有效地靶向这些神经通路来促进甲基苯丙胺依赖的药物开发。