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.
The proposed research will evaluate the effects of adding a structured exercise training program to treatment for methamphetamine use disorder in clients who are receiving behavioral therapy for their addiction. The goals are to determine the effects of an exercise intervention on brain dopamine receptors and on cognitive functions that have been linked to these receptors, and to determine if positive effects of exercise on therapeutic outcomes are related to changes in dopamine receptors and cognition. The project offers to improve the approach to treatment for methamphetamine use disorder, a significant public health problem for which there is no FDA-approved medication.