Exercise in Methamphetamine Use Disorder: Dopamine Receptor Upregulation and Neural Function

甲基苯丙胺使用障碍的运动：多巴胺受体上调和神经功能

基本信息

批准号：
10398834
负责人：
Edythe Danick London
金额：
$ 63.59万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10398834
关键词：
Abstinence Aftercare Amphetamines Attention Behavior Therapy Binding Brain Brain Chemistry Cessation of life Client Cognition Cognitive Control Groups Corpus striatum structure Crime DRD2 gene DSM-V Data Decision Making Dopamine Dopamine Agonists Dopamine Receptor Drug Modelings Economic Burden Educational Intervention Exercise FDA approved Female Functional Magnetic Resonance Imaging Gender Goals Health education Image Impulsivity Individual Intervention Laboratories Learning Left Link Measures Methamphetamine Methamphetamine use disorder Motor Neurocognitive Neuronal Plasticity Neurophysiology - biologic function Outcome Outcome Measure Participant Pathology Patient Self-Report Performance Pharmaceutical Preparations Pharmacotherapy Positron-Emission Tomography Public Health Randomized Reporting Research Resources Reversal Learning Self-control as a personality trait Severities Short-Term Memory Signal Transduction Stimulant Structure Supervision Task Performances Testing Therapeutic Time Training Programs Up-Regulation Urine Visit Work addiction cognitive control cognitive function cognitive testing dopamine system executive function exercise intensity exercise intervention exercise program exercise training flexibility follow-up group intervention hazard improved improved functioning indexing male methamphetamine use methamphetamine user negative affect neurobehavioral nonmedical use novel strategies outcome prediction programs receptor receptor upregulation relating to nervous system response sex simulation stimulant dependence stimulant use disorder success therapeutic target therapy outcome treatment effect treatment program virtual

项目摘要

PROJECT SUMMARY/ABSTRACT With no approved medications for methamphetamine (MA) use disorder, a major public health problem, new treatment approaches are needed. Striatal dopamine D2-type receptor (DRD2/3) availability (binding potential, BPND) is linked to indices of cognitive control, and MA users show deficits in both. Striatal DRD2/3 BPND release can predict outcomes of behavioral treatments for stimulant dependence. Thus, DRD2/3 signaling is a logical therapeutic target, but dopamine agonists have not been successful treatments, perhaps due to underlying pathology involving DRD2/3. We suggest that promoting dopaminergic neuroplasticity may ameliorate neurobehavioral problems associated with MA use disorder. Our preliminary data indicate that adding an exercise program can increase striatal DRD2/3 BPND in MA users receiving behavioral treatment. If such an increase can improve neurocognitive function, it may be a useful therapeutic adjunct for stimulant use disorders. We have shown that in healthy control subjects, striatal DRD2/3 BPND is linked with performance and neural activity related to self-control and cognitive flexibility. To determine whether exercise can improve function in these and other cognitive domains, we will randomize individuals with MA use disorder (males and females, 18-45 years) in a residential behavioral treatment program to two groups: 1) Exercise-Group participants will be in an 8-week, moderate-intensity exercise training program; 2) Control-Group participants will be in parallel health-education sessions with equal time and supervision. We will assess DRD2/3 BPND with PET, and neural activity in tests of inhibitory control and cognitive flexibility during fMRI. We have four specific aims: 1) confirm that adding exercise to behavioral treatment produces striatal DRD2/3 upregulation in MA users; 2) compare effects of the exercise and control conditions on performance and associated neural activity during tests of inhibitory control and cognitive flexibility, and on performance in a cognitive battery; 3) test whether effects on cognitive control and brain function are related to changes in DRD2/3 BPND; and 4) compare the effects of the exercise and control conditions on simulated MA choice and actual MA use. We expect that: 1) BPND will increase more in the exercise condition than the control condition; 2) the exercise group will show more improvement than the controls in task performance and activation within executive-control regions during fMRI, and in performance on a cognitive test battery; 3) DRD2/3 BPND increases in exercise-group participants will be positively associated with changes in task performance and neural activity; and 4) both virtual MA choice, measured in the laboratory, and MA use, measured by self-report and urine tests at follow-up, will be lower in participants in the exercise group and will be negatively related to DRD2/3 BPND at the end of the intervention. The use of exercise training as a way to alter brain chemistry and function in individuals with MA use disorder is a novel approach with the potential to provide mechanistic information that ultimately may help inform treatment.

项目概要/摘要由于没有批准治疗甲基苯丙胺（MA）使用障碍这一重大公共卫生问题的药物，需要新的治疗方法。纹状体多巴胺 D2 型受体 (DRD2/3) 可用性（结合潜力（BPND）与认知控制指数相关，MA 用户在这两个方面都表现出缺陷。纹状体 DRD2/3 BPND 释放可以预测兴奋剂依赖行为治疗的结果。因此，DRD2/3 信号传导是一个合乎逻辑的治疗目标，但多巴胺激动剂尚未成为成功的治疗方法，可能是由于涉及 DRD2/3 的潜在病理学。我们认为促进多巴胺能神经可塑性可能改善与 MA 使用障碍相关的神经行为问题。我们的初步数据表明添加锻炼计划可以增加接受行为治疗的 MA 用户的纹状体 DRD2/3 BPND。如果这种增加可以改善神经认知功能，它可能是兴奋剂使用的有用治疗辅助剂失调。我们已经证明，在健康对照受试者中，纹状体 DRD2/3 BPND 与表现和表现相关。与自我控制和认知灵活性相关的神经活动。确定运动是否可以改善在这些和其他认知领域的功能中，我们将随机分配患有 MA 使用障碍的个体（男性和女性，18-45岁）参加住院行为治疗计划，分为两组：1）运动组参与者将接受为期8周的中等强度运动训练计划； 2) 对照组参与者将在同等时间和监督下同时举办健康教育课程。我们将评估 DRD2/3 BPND PET 以及功能磁共振成像期间抑制控制和认知灵活性测试中的神经活动。我们有四个具体的目标：1) 确认在行为治疗中添加运动会导致 MA 中纹状体 DRD2/3 上调用户； 2) 比较运动和控制条件对表现和相关神经活动的影响在抑制控制和认知灵活性测试以及认知电池表现期间； 3）测试对认知控制和大脑功能的影响是否与 DRD2/3 BPND 的变化有关； 4）比较练习和控制条件对模拟 MA 选择和实际 MA 使用的影响。我们期望： 1）BPND在运动条件下比控制条件下增加更多； 2）练习组将展示在执行控制区域内的任务绩效和激活方面比控制有更多的改进 fMRI 以及认知测试电池的表现； 3) 运动组参与者的 DRD2/3 BPND 增加与任务表现和神经活动的变化呈正相关； 4) 两个虚拟 MA 在实验室测量的选择，以及通过自我报告和随访时尿液测试测量的 MA 使用，将被运动组参与者的比例较低，并且在训练结束时与 DRD2/3 BPND 呈负相关干涉。使用运动训练来改变 MA 患者的大脑化学和功能使用障碍是一种新颖的方法，有可能提供最终可能有所帮助的机械信息告知治疗。