Comparison of the effects of various typical and atypical antipsychotic drugs on the suppressant action of 2-methylserotonin on medial prefrontal cortical cells in the rat.

In this study, we report the effects of various typical and atypical antipsychotic drugs (APDs) on the suppressant action of microiontophoretically applied 2-methylserotonin (2-Me-5HT, a 5-HT3 agonist) on medial prefrontal cortical (mPFc) cells. The microiontophoresis of 2-Me-5HT (10-80 nA) produced a current-dependent suppression of mPFc cells' firing, and this effect was blocked by various 5-HT3 antagonists. The microiontophoresis of the atypical APDs clozapine and a structurally related compound, RMI 81,582, mimicked the action of the 5-HT3 antagonists. In addition, the intravenous administration of clozapine and RMI 81,582 antagonized the suppressant action produced by the iontophoretic application of 2-Me-5HT on mPFc cells. However, the suppressant action of 2-Me-5HT was not blocked by the typical APDs haloperidol and chlorpromazine. The putative atypical APDs risperidone, setoperone, CL 77328, SCH 23390, CGS 10746B, 1-sulpiride, and thioridazine were ineffective in antagonizing 2-Me-5HT's action. Overall, our results suggest that the majority of putative atypical APDs do not interact with 5-HT3 binding sites in the brain. Whether the interaction of clozapine and RMI 81,582 with 5-HT3 sites is correlated with their therapeutic efficacy or lower potential to induce neurological side effects remains to be determined.