Low doses of the atypical antipsychotic drug risperidone are effective in patients with obsessive compulsive disorder (OCD) not responding to serotonin (5-HT) reuptake inhibitors, although higher doses have been reported to induce OCD symptoms in psychotic patients. Since such atypical antipsychotics exert, in addition to dopamine, 5-HT2 receptor antagonistic properties, it was deemed essential to investigate the electrophysiological effect of these agents on 5-HT2 receptors in the rat orbito-frontal cortex (OFc), a brain region implicated in OCD. Microiontophoretic application of the GABAA receptor antagonist bicuculline had no effect on the suppressant effect of neuronal activity in the OFc induced by microiontophoretic application of the preferential 5-HT2A and 5-HT2C receptor agonists (+)-1-(4-iodo-2, 5-dimethoxyphenyl)-2-aminopropane (DOI) and m-chlorophenyl-piperazine (mCPP), respectively, but it antagonized the effect of GABA on the same neurons. These results indicate a lack of involvement of GABA interneurons in the suppressant effect of DOI and mCPP. While the 5-HT2 receptor antagonist ritanserin (2 mg/kg, i.v.) attenuated the inhibitory effect of DOI and mCPP in the medial prefrontal cortex (mPFc), the inhibition was unaffected in the OFc. In the mPFc, the effect of DOI and mCPP was blocked by both clozapine (1.0 and 10 mg/kg, i.v.) and risperidone (0.1 and 1.0 mg/kg, i.v.). In the OFc, only the suppressant effect of mCPP was attenuated by both doses of clozapine but only by the high dose of risperidone. These results suggest that the 5-HT2 response in the OFc is more akin to the 5-HT2C subtype and that the deleterious effect sometimes observed with high doses of risperidone and clozapine may be due to a decrease in 5-HT neurotransmission. In contrast, the beneficial effect of low doses of risperidone may be due, in part, to the antagonism of dopamine receptors.