In vivo microdialysis was used to investigate the mechanism behind the increase in extracellular dopamine (DA) induced by increase in extracellular serotonin (5-HT) level and 5-HT1 and 5-HT2 receptor activation. The following serotoninergic drugs were perfused in the absence or presence of nomifensine (5 microM) or tetrodotoxin (TTX; 2 microM): clomipramine (10, 500 and 1,000 microM), a selective 5-HT reuptake inhibitor; 8-OH-DPAT (50 and 500 microM), a 5-HT1A receptor agonist; and alpha-methyl-5-HT (1, 5 and 50 microM), a 5-HT2 receptor agonist. All the serotoninergic drugs studied increased DA extracellular output in a dose-dependent manner. The presence of nomifensine attenuated the effect of perfusion of clomipramine (500 microM) and completely abolished the effect of perfusion of 8-OH-DPAT (500 microM) and alpha-methyl-5-HT (5 microM) on DA extracellular output. Clomipramine (100-1,000 microM) perfusion produced a dose dependent increase in DOPAC extracellular output, which was stronger when clomipramine (500 microM) was co-perfused with nomifensine. 8-OH-DPAT and alpha-methyl-5-HT perfusion decreased DOPAC overflow. Addition of TTX to the perfusion fluid one hour before serotoninergic drugs perfusion, did not completely abolish the effect on dopamine extracellular output produced by the serotoninergic drugs. These data seem to indicate that increase in extracellular 5-HT level and 5-HT1 and 5-HT2 receptor activation increase in vivo DA extracellular output in the striatum mainly by a nonexocytotic mechanism involving DA uptake sites and, secondarily, by activation of 5-HT receptors.