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）：甲基苯丙胺的使用障碍代表了一个重要且昂贵的公共健康问题，但有效的甲基苯丙胺依赖性药物疗法仍然难以捉摸。 Naltrexone是一种由FDA批准的阿片受体拮抗剂，对MU受体的亲和力最大，并且在较小但有意义的Kappa和Delta受体中，代表了一种潜在的有效药物，用于治疗甲基苯丙胺依赖性。临床前和临床数据表明纳曲酮可有效减少苯丙胺的渴望。但是，这种效应的神经机制仍然未知。此外，编码MU-Apoid受体的个体OPRM1基因型可能会起作用纳曲酮对甲基苯丙胺提示引起的渴望的影响。拟议的NRSA应用的总体目的是通过研究Naltrexone对Naltrexone的神经生物学作用来促进我作为临床神经科学家的发展 甲基苯丙胺依赖性个体中有和没有ASP40变体的甲基苯丙胺提示。为此，将对甲基苯丙胺依赖性的15个个体进行基因分型，并接受fMRI方案，其中提供了视觉甲基苯丙胺和对照线索。参与者将在Naltrexone（50mg）的目标剂量上进行两次扫描，一次在安慰剂上进行扫描。这15名参与者的数据将与我的赞助商（n = 15）在正在进行的R21中获取的数据结合使用，用于最终的30个甲基苯丙胺依赖人的样本。全脑造影剂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提示提示引起的渴望的途径。 OPRM1基因型以及Kappa和三角洲阿片受体多态性将被测试为对纳曲酮与安慰剂的神经影像反应的主​​持人。此外，所有分析都将使用动脉自旋标记（ASL）控制药物改变大脑血流。该转化项目的结果将通过评估甲基苯丙胺渴望的途径以及测试纳曲酮是否有效靶向这些神经途径来提高甲基苯丙胺依赖性的药物开发。