Ventrostriatal Dopamine Release and Reward Motivation in MDD

Better understanding of the basic neurobiology of mood dysfunction appears necessary to enable further progress in the treatment of depression. Reward motivation (and the closely related construct of "reward learning") is a core neurobehavioral domain.(1,2) In major depressive disorder (MDD), low reward motivation is a key aspect of anhedonia, a cardinal symptom of MDD, and is related to resistance to treatment.(2,3) Although much has been learned about reward motivation's neurobiology and relevance to psychopathology, important gaps in our knowledge have impeded the application of basic science findings to improving treatment of MDD. Reward motivation in healthy subjects involves ventrostriatal (VST) dopamine (DA)(4,5), and reduced reward motivation is linked to MDD and anhedonia.(3,6) These data suggest that VST DA dysfunction might be present in MDD and manifested clinically by anhedonia. While DA neuroreceptor imaging studies have failed to verify this, they have been methodologically compromised. Limitations include imaging methods with poor resolution of functional striatal subregions, MDD samples heterogeneous for antidepressant use, and use of self-report measures of anhedonia, rather than objective behavioral testing of the specific domain of reward motivation. This will be the first study of both VST DA release (by PET imaging) and reward motivation, and will include patients with MDD and healthy volunteers. Reward motivation will be captured and operationalized as reward learning in a probabilistic reward task (prior to imaging). This will clarify if VST DA dysfunction is linked to impaired motivation in MDD. To test clinical implications in MDD patients, we will assess the relationship of VST DA release, reward motivation, and anhedonia to outcome of subsequent open label treatment with the DA D2 receptor agonist pramipexole.