Given the paucity of advances in the treatment of mood disorders in recent years, a better understanding of the basic neurobiology of mood dysfunction seems needed for further progress. Reward motivation (and the closely related construct of reward learning) is a core neurobehavioral domain that is central to depression. Although much has been learned about the neurobiology of reward motivation, important gaps in knowledge impede the application of basic science findings to improving treatment of major depressive disorder (MDD). Reward motivation in healthy subjects involves ventrostriatal (VST) dopamine (DA), and impaired reward motivation is linked to MDD and anhedonia. These data suggest that VST DA dysfunction might be present in MDD and manifested clinically by anhedonia. Our preliminary data show that impaired reward motivation is related to MDD diagnosis, anhedonia, and persistence of MDD, and is modulated by single doses of the DA agonist pramipexole. Our preliminary data also show that amphetamine-induced DA release is low in the VST in MDD, particularly for drug-naive patients. It remains unclear, however, whether VST DA release is a mechanism of reward motivation in MDD, and whether VST DA release and reward motivation might specifically predict response to antidepressants targeted to increase VST DA transmission. This R01 will test if DA release in the VST is related to reward motivation and treatment outcome in MDD. Our approach capitalizes on advances in neuroreceptor imaging and behavioral neuroscience to learn how striatal DA contributes to low motivation in MDD. We propose the first study of both VST DA release (using neuroreceptor PET imaging) and reward motivation (using a validated probabilistic reward task) in MDD patients. VST DA release is a promising target for drug or behavioral treatments because it responds to drug and behavioral probes. To test the clinical implications of these features, we will assess the relationship of VST DA release, reward motivation, and anhedonia to the clinical outcome of treatment with the DA D2 receptor agonist pramipexole, which has been shown to have antidepressant properties. Consistent with NIMH RDoC interim guidance, this proposal uses a core behavioral dimension (reward learning), and multiple units of analysis (molecules, circuits, behavior, self report); proposed analyses are dimensional and categorical. Drug-naive patients with MDD (n=27) and healthy comparison (HC) subjects (n=27) will complete testing for DA release in the VST using [11C]raclopride PET pre- and post-amphetamine, and they will be assessed for reward learning using a probabilistic reward task. After imaging, MDD patients will be offered 6 weeks of open label treatment with pramipexole to obtain proof-of-concept data on DA release, reward motivation, and self-reported anhedonia as predictors of treatment response. If VST DA release and reward motivation are associated with response to this novel targeted treatment, it would spearhead development of a novel class of treatments for MDD and a broad spectrum of difficult-to-treat conditions characterized by low motivation.