The putative atypical antipsychotic drug amperozide (APZ) shows high affinity for serotonin 5-HT2 receptors but only low affinity for dopamine (DA) D2 receptors. By employing microdialysis, we examined the effects of APZ on extracellular concentrations of DA in the nucleus accumbens (NAC), the dorsolateral striatum (STR) and the medial prefrontal cortex (MPC) of awake rats. A 5.0 mg/kg (SC) dose of APZ failed to affect DA concentrations in the NAC, while it increased DA outflow in the STR (by 46%) and the MPC (by 207%). A higher dose of APZ (10 mg/kg, SC) enhanced dialysate DA from the NAC and the STR by 30%, and from the MPC by 326%. Similarly, clozapine (2.5 and 10 mg/kg, SC) produced a greater release of DA in the MPC (+ 127 and + 279%) than in the NAC (+ 52 and + 98%). The selective 5-HT2 receptor antagonist ritanserin (1.5 and 3.0 mg/kg, SC) also produced a slightly higher increase of DA output in the MPC (+ 25 and + 47%) compared with the NAC (+ 19 and + 21%). In contrast, the selective D2 receptor antagonist raclopride (0.5 and 2.0 mg/kg, SC) increased DA release in the NAC (+ 65 and + 119%) to a greater extent than in the MPC (+ 45 and + 67%). These data suggest that the 5-HT2 receptor antagonistic properties of APZ and clozapine may contribute to their preferential effects on DA transmission in the MPC. Infusion of low doses (1, 10 microM, 40 min) of APZ through the probe in the DA terminal areas did not affect significantly DA outflow, while infusion of high doses (100, 1000 microM, 40 min) resulted in a more pronounced elevation of DA levels in the NAC (up to 961%) and the STR (up to 950%) than in the MPC (up to 316%). These findings indicate that the selective action of systemically administered APZ on DA in the MPC is most likely mediated at a level other than the terminal region. Taken together, the present results provide support for the notion that 5-HT2 receptor antagonism may be of considerable significance for the action of atypical antipsychotic drugs on mesolimbocortical dopaminergic neurotransmission.