Dopaminergic modulation of frontostriatal function

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DESCRIPTION (provided by applicant): The nigrostriatal and mesocortical dopamine systems are well known to play an important role in the cognitive processes of working memory and cognitive control. However, accumulating evidence indicates that the effects of dopaminergic drugs are complex: They can improve or impair cognitive function. Such contrasting effects have been observed both in young healthy volunteers, as well as in patients with Parkinson's disease (PD), a movement disorder characterized by severe dopamine depletion. Recent progress reveals that the relationship between dopamine and cognitive performance is qualified by at least three factors. First, drug effects appear dependent on the type of task: while administration of dopaminergic drugs can improve performance on some tasks, it can simultaneously impair performance on other tasks in the same subjects. Second, the effects vary depending on dopamine receptor selectivity of the drug under study. Thus, stimulation of dopamine D1 and D2 receptors has dissociable effects on distinct cognitive functions. Third, dopaminergic drugs can improve function in some individuals while impairing the same function in other individuals. The proposed experiments aim to characterize these complex, sometimes paradoxical effects of dopaminergic drugs in both healthy subjects and PD patients as a function of task demands, receptor specificity and individual differences in baseline capacity. Both performance and brain activity (using fMRI and PET) will be assessed. More specifically, drug effects are predicted to differ depending on whether the task requires motor versus cognitive processes, and whether the task requires cognitive flexibility versus cognitive stability. We predict that these dissociable effects reflect differential modulation by dopamine of striatal versus prefrontal brain regions. In addition, they may reflect differential modulation by dopamine at D1 and D2 receptors. Finally, drug effects are hypothesize to differ depending on individual variation in baseline working memory capacity, associated with baseline dopamine function. Dopamine is of fundamental importance to the etiology of a wide variety of neurobehavioral disorders such as PD, attention deficit hyperactivity disorder, schizophrenia and drug addiction. A further understanding of the relationship between dopamine and cognition should further our understanding of the mechanisms underlying cognitive and behavioral deficits in these disorders and provide insight into novel approaches to treating such deficits with medications targeted at specific neurotransmitter systems.