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: 8825903
• 负责人: Kelly Elizabeth Courtney
• 金额: $ 3.02万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8825903
• 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和昂贵的公共卫生问题，但有效的药物治疗甲基苯丙胺依赖仍然难以捉摸。纳曲酮是一种经fda批准的阿片受体拮抗剂，对mu受体具有最大的亲和力，对kappa和delta受体具有较小但有意义的亲和力，代表了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能有效减少对安非他明的渴望；然而，这种效应背后的神经机制尚不清楚。此外，一个人的OPRM1基因型，编码mu-阿片受体，可能起到调节纳曲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曲酮对神经生物学的影响来促进我作为临床神经科学家的发展