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

项目摘要/摘要 由于没有获得批准的治疗甲基苯丙胺(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(DRD2/3)的可用性(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DRD2/3 BPND的释放可以预测兴奋剂依赖行为治疗的结果。因此，DRD2/3信号 是一个合乎逻辑的治疗靶点，但多巴胺激动剂一直没有成功治疗，可能是由于 涉及DRD2/3的潜在病理。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。我们的初步数据显示 在接受行为治疗的MA使用者中，增加运动计划可以增加纹状体DRD2/3 BPND。如果 这种增加可以改善神经认知功能，它可能是一种有用的刺激剂使用的治疗辅助 精神错乱。我们已经证明，在健康对照组受试者中，纹状体DRD2/3 BPND与表现和 神经活动与自我控制和认知灵活性有关。来确定运动是否能改善 在这些和其他认知领域的功能，我们将随机选择患有MA使用障碍的个体(男性和 18-45岁的女性)参加住宅行为治疗计划，分为两组：1)运动组 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同时举行健康教育会议。我们将使用以下工具评估DRD2/3 BPND 在fMRI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)证实在行为治疗的基础上增加运动可使MA患者纹状体DRD2/3表达上调 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的测试中，以及在认知电池中的表现；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；以及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。我们预计： 1)运动状态下BPND较对照状态增加更多；2)运动组表现为 在执行控制区域内的任务绩效和激活度方面比控制组有更大的改善 3)运动组参与者DRD2/3 BPND增加 将与任务绩效和神经活动的变化正相关；以及4)两者都是虚拟MA 在实验室中测量的选择，以及通过自我报告和后续尿检测量的MA使用，将是 在运动组参与者中较低，并将在运动结束时与DRD2/3 BPND负相关 干预。运动训练作为改变MA患者脑化学和功能的一种方法 使用障碍是一种新的方法，有可能提供机械性的信息，最终可能会有所帮助 通知治疗。

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.