The effect of the selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor, fluoxetine (10 mg/kg s.c.), two tricyclic antidepressants, clomipramine (10 mg/kg s.c.) and imipramine (10 mg/kg s.c.), and vehicle on extracellular dopamine levels was studied in rat nucleus accumbens and striatum by in vivo microdialysis. Fluoxetine produced significant decreases in extracellular dopamine levels in both the nucleus accumbens and striatum (mean maximum percentage decrease: 58% and 57% of pre-drug baseline, respectively). In contrast, imipramine and clomipramine significantly increased extracellular dopamine in the striatum (148% and 150%, respectively) compared to the effect of vehicle alone (118%). These results suggest that the selective serotonin reuptake inhibitor, fluoxetine, and the tricyclic antidepressants, clomipramine and imipramine, affect dopaminergic activity in diverse ways and in a region-specific manner. Thus, the antidepressant effect of these drugs is unlikely to be related to their acute effects on dopaminergic neurotransmission. The differential effects of the selective serotonin reuptake inhibitor and tricyclic antidepressants on extracellular dopamine could account for other differences in their clinical and side effect profiles. Further studies of the chronic effects of the selective serotonin reuptake inhibitor and the tricyclic antidepressants on dopaminergic activity are required to elucidate the role of dopamine in the antidepressant effect.