PROJECT SUMMARY Methamphetamine (MA) Use Disorder Deficits in dopamine signaling and cognitive function are observed in Methamphetamine (MA) Use Disorder, which have been linked to reduced dopamine D2-type receptor (DRD2/3) availability (binding potential: BPND) in the striatum. MA use is also associated with abnormal functional connectivity at rest within dopaminergic circuitry, which in turn is associated with impaired decision making. The shared neural abnormalities linked with chronic MA use and impairments in self-control and decision-making suggest that treatments focused on repairing DRD2/3 signaling, and connectivity and activity within mesocorticolimbic circuitry may decrease maladaptive decision-making and improve inhibitory control to reduce subsequent MA use. Given that higher BPND has been linked to resilience to addiction in humans and to greater success of behavioral treatments for stimulant dependence, enhancing striatal DRD2/3 signaling may be a useful therapeutic approach for stimulant addiction. The goal of this project is to test the potential of varenicline as a therapeutic target to repair deficits in dopamine signaling and cognitive performance observed in MA Use Disorder. Varenicline administration produces striatal DRD2/3 upregulation in drug-nave rats, but whether varenicline has the same effect in humans is not known. Varenicline also improves cognitive performance in human subjects, and because cognitive deficits can undermine behavioral treatments, improvement with varenicline, either through DRD2/3 upregulation or another mechanism, may provide a useful adjunct to behavioral treatments for addictions as well as other disorders which feature deficits in DRD2/3. The potential therapeutic effects of varenicline treatment will be assessed in healthy human subjects with methamphetamine-use disorder, using a placebo-controlled double-blind design. The dependent variables will be DRD2/3 BPND in striatum, measured using positron emission tomography, mesocorticolimbic functional connectivity at rest, measured using functional magnetic resonance imaging, and cognitive performance in tests of reward-based decision making and cognitive control and flexibility. The results of this research have the potential to advance the design and development of therapeutic targets for treating stimulant use disorders and other neuropsychiatric problems featuring DRD2/3 deficits.