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

项目总结/摘要 由于没有批准用于甲基苯丙胺（MA）使用障碍的药物，这是一个主要的公共卫生问题， 需要新的治疗方法。纹状体多巴胺D2型受体（DRD 2/3）可用性（结合 潜在的，BPND）与认知控制指数有关，MA使用者在这两个方面都表现出缺陷。纹状体DRD 2/3 BPND释放可以预测兴奋剂依赖行为治疗的结果。因此，DRD 2/3信号传导 是一个合乎逻辑的治疗目标，但多巴胺激动剂还没有成功的治疗，也许是由于 涉及DRD 2/3的基础病理学。我们认为，促进多巴胺能神经可塑性， 改善与MA使用障碍相关的神经行为问题。我们的初步数据显示， 在接受行为治疗的MA使用者中，增加锻炼计划可以增加纹状体DRD 2/3 BPND。如果 这种增加可以改善神经认知功能，它可能是用于兴奋剂用途有用的治疗辅助剂 紊乱我们已经证明，在健康对照组中，纹状体DRD 2/3 BPND与表现有关， 与自我控制和认知灵活性相关的神经活动。为了确定运动是否能改善 在这些和其他认知领域的功能，我们将随机分配患有MA使用障碍的个体（男性和女性）。 女性，18-45岁）在住宅行为治疗计划中分为两组： 参与者将参加为期8周的中等强度运动训练计划; 2）对照组参与者 将在平等的时间和监督下参加平行的健康教育课程。我们将评估DRD 2/3 BPND， PET，以及功能磁共振成像中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 目的：1）证实在行为治疗中加入运动会导致MA患者纹状体DRD 2/3上调 2）比较锻炼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期间，以及在认知电池中的表现; 3）测试 对认知控制和脑功能的影响是否与DRD 2/3 BPND的变化有关;以及4）比较 运动和控制条件对模拟MA选择和实际MA使用的影响。我们期望： 1)运动状态下的BPND比对照状态下增加更多; 2）运动组表现出 执行控制区域内的任务绩效和激活比对照组有更多的改善， 3）运动组参与者的DRD 2/3 BPND增加 将与任务表现和神经活动的变化呈正相关; 4）虚拟MA 在实验室中测量的选择，以及通过随访时的自我报告和尿液检查测量的MA使用，将 运动组的参与者较低，并将与DRD 2/3 BPND在结束时呈负相关。 干预使用运动训练作为改变MA患者脑化学和功能的一种方式 使用障碍是一种新的方法，有可能提供机制信息，最终可能有助于 告知治疗。

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.