We investigated the effect of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on l-3,4-dihydroxyphenylalanine (l-DOPA)-derived extracellular dopamine (DA) levels in the striatum of rats with nigrostriatal dopaminergic denervation using in vivo microdialysis. Treatment with fluoxetine (10 mg/kg i.p.) induced a 41% reduction in the cumulative amount of extracellular DA during 300 min following l-DOPA administration (50 mg/kg i.p.). This effect was antagonized by pretreatment with WAY-100635, a potent 5-HT1A antagonist, indicating that this effect of fluoxetine is due to its 5-HT1A agonistic property. These results suggest that SSRIs may impair motor functions in patients with Parkinson's disease (PD) by reducing efflux of exogenous l-DOPA-derived DA.