The effects of (+-)-DOI (1-(2,5-dimethoxy-4-iodophenyl)-aminopropane) hydrochloride, a mixed 5-HT2A/2C receptor agonist, on the release of dopamine (DA) following D-amphetamine sulfate (AMP) or a DA D2 autoreceptor selective dose of (-)-apomorphine hydrochloride (APO), were investigated in rat striatum (STR) and nucleus accumbens (NAC), using in vivo microdialysis. AMP (1.0 mg/kg, s.c.) produced marked increases in extracellular DA levels in both the STR and the NAC whereas DOI (2.5 mg/kg, i.p.) alone had no significant effect on extracellular DA levels in either region. Pretreatment with DOI 30 min prior to AMP, further enhanced the AMP-induced increase in striatal extracellular DA levels. On the other hand, DOI pretreatment attenuated the APO (50 micrograms/kg, s.c.)-induced decrease in extracellular DA levels in the STR. Pretreatment with DOI did not affect the ability of either AMP or APO to modulate extracellular DA levels in the NAC. These results provide further evidence that 5-HT2A/2C receptors modulate the release mechanisms of DA in the STR. Possible mechanisms are discussed.