Positron emission tomography and in vivo microdialysis were used to study serotonin's role in modulating striatal dopamine. Serial PET studies were performed in adult female baboons at baseline and following drug treatment, using the dopamine (D2) selective radiotracer, 11C-raclopride. The serotonergic system was manipulated by administration of the selective 5-HT reuptake inhibitor, citalopram, or by serotonergic (5-HT2) receptor blockade (using altanserin, a 5-HT2 antagonist). 11C-Raclopride time-activity data from striatum and cerebellum were combined with plasma arterial input functions and analyzed by calculating a distribution volume as described previously (Logan et al., 1990). Additionally, in vivo microdialysis studies were performed in awake freely moving rats using similar pharmacologic challenges plus SR 46349B, a new highly selective 5-HT2 receptor antagonist. Altanserin and SR 46349B increased extracellular striatal dopamine concentrations (35% and 910%, respectively) while altanserin decreased striatal 11C-raclopride binding (37%). Citalopram, however, decreased extracellular striatal dopamine concentrations (50%) and increased 11C-raclopride binding (33%). These data demonstrate that 5- HT-selective drugs produce changes in striatal dopamine that can be measured noninvasively with PET. Furthermore, the PET data obtained from anesthetized baboons is consistent with in vivo microdialysis data obtained from awake and freely moving rats. Finally, these studies have implications for understanding the therapeutic efficacy of atypical neuroleptics and their utility for treating schizophrenia and affective disorders.