The effect of typical and atypical antipsychotic drugs on the stimulation of phosphoinositide hydrolysis produced by the 5-HT3 receptor agonist 2-methyl-serotonin

The atypical antipsychotic drug clozapine (CLOZ) and a structurally related compound RMI 81,582 (RMI) dose-dependently inhibited the stimulation of phosphoinositide hydrolysis induced by the 5-HT₃ receptor agonist 2-methyl-serotonin in the rat fronto-cingulate and entorhinal cortices. The antagonism of 2-methyl-serotonin's stimulation of phosphoinositide hydrolysis by CLOZ and RMI was comparable to that observed with 5-HT₃ antagonists such as granisetron, ondansetron, ICS 205–930 and zacopride. By contrast, the typical antipsychotic drugs haloperidol (HAL) and chlorpromazine (CPZ) did not antagonize the stimulation of phosphoinositide hydrolysis induced by 2-methyl-serotonin. The 5-HT₃ receptor antagonizing effect of CLOZ and RMI may contribute to the ‘atypical’ pharmacological profile of these antipsychotic drugs.