We have previously reported that repeated dosing with the selective serotonin reuptake inhibitor (SSRI) citalopram decreases striatal [11C]raclopride binding in healthy volunteers. As the SSRI-class antidepressant drugs are believed to have a similar mechanism of action, we wanted to explore whether the prototype SSRI drug, fluoxetine, shares the effects of citalopram on subcortical dopamine neurotransmission. Eight healthy male volunteers were studied using a randomized double-blind placebo-controlled study design. Striatal and thalamic D2-receptor binding was measured at baseline, after a single oral dose (20 mg) of fluoxetine, and after repeated dosing (2 wk, 20 mg/d). The D2-receptor binding potential (BP) was assessed using [11C]raclopride and 3D positron emission tomography. Repeated dosing of fluoxetine decreased BP in the right medial thalamus (p=0.022). Fluoxetine did not decrease striatal BP, but there was a trend (p=0.090) towards increased BP in the left putamen after repeated dosing. A single dose of fluoxetine did not affect BP in the thalamus or striatum. Fluoxetine appears to have a regionally selective effect on the dopaminergic neurotransmission in various areas of the brain. The current results after fluoxetine together with our previous data on citalopram suggest that the modulatory effects of these drugs on striatal dopaminergic neurotransmission are different upon repeated dosing and further substantiates pharmacological differences between SSRI-class drugs.