A serotonin (5-HT)1A receptor partial agonist, buspirone, potentiates the clinical antidepressant properties of 5-HT reuptake inhibitors (SSRIs). Herein, we examined the interaction of buspirone with two SSRIs, duloxetine and fluoxetine, on extracellular levels of 5-HT, dopamine (DA), and noradrenaline (NAD) in single dialysate samples of freely moving rats. Duloxetine (5.0 mg/kg. s.c.) and fluoxetine (10.0 mg/kg, s.c.) increased dialysate levels of DA (65 and 60% vs. basal values, respectively). NAD (400 and 90%, respectively), and 5-HT (130 and 110%, respectively) in the frontal cortex (FCX). Buspirone (2.5 mg/kg, s.c.) similarly elevated levels of DA (100%) and NAD (160%) but reduced those of 5-HT (-50%). Administered with buspirone, the ability of duloxetine and fluoxetine to increase 5-HT levels was transiently inhibited (over 60 min), although by the end of sampling (180 min) their actions were fully expressed. In contrast, buspirone markedly and synergistically facilitated the elevation in DA levels elicited by duloxetine (550%) and fluoxetine (240%). Furthermore, buspirone potentiated the induction of NAD levels by duloxetine (750%) and fluoxetine (350%). These data suggest that a reinforcement in the influence of SSRIs on DA and possibly. NAD but not 5-HT release in FCX may contribute to their increased antidepressant activity in the presence of buspirone. More generally, they support the hypothesis that a reinforcement in dopaminergic transmission in the FCX contributes to the actions of SSRIs and other antidepressant drugs.