HALOPERIDOL AND CLOZAPINE TREATMENT AND THEIR EFFECT ON M-CHLOROPHENYLPIPERAZINE-MEDIATED RESPONSES IN SCHIZOPHRENIA - IMPLICATIONS FOR THEMECHANISM OF ACTION OF CLOZAPINE

Since clozapine is, in contrast to conventional neuroleptics, effectiv e in treatment refractory schizophrenic patients its mechanism of acti on may be different from that of typical neuroleptics. Clozapine has b een shown to display the highest binding affinity of all neuroleptics to one of the serotonin (5-hydroxytryptamine, 5HT) receptor subtypes, i.e., the 5HT1c receptor. Furthermore, clozapine, in contrast to conve ntional neuroleptics, blocks the effect of 5HT agonists on ACTH and co rticosterone release in animals. This study hypothesized that clozapin e, but not haloperidol would block ACTH and prolactin release induced by the 5HT agonist, m-chlorophenylpiperazine (MCPP). MCPP (0.35 mg/kg PO) was administered after a 3-week drug-free period, after 5 weeks of haloperidol treatment (20 mg/day) and finally after 5 weeks of clozap ine treatment (> 400 mg/day) in ten male schizophrenic patients. Cloza pine, but not haloperidol, blocked the effect of MCPP on ACTH and prol actin release. These results suggest that clozapine, in contrast to ha loperidol, is a functional 5HT antagonist. Since MCPP-induced ACTH and prolactin release may be (partially) 5HT1c mediated, these results su ggest that clozapine is a potent antagonist at the 5HT1c receptor.