Effects of antipsychotic drugs on neurotoxicity, expression of fos-like protein and c-fos mRNA in the retrosplenial cortex after administration of dizocilpine

In this study, we examined the effect of clozapine, olanzapine, risperidone and haloperidol on the neuropathology (i.e. neuronal vacuolization) and th e expression of Fos-like protein and c-fos mRNA in the retrosplenial cortex of female Sprague-Dawley rats induced by the NMDA receptor antagonist dizo cilpine. Pretreatment (15 min) with clozapine or olanzapine, but not risper idone or haloperidol, blocked the neuronal vacuolization produced by dizoci lpine (0.5 mg/kg, s.c.) in the rat retrosplenial cortex in a dose-dependent manner. Furthermore, pretreatment (15 min) with clozapine or olanzapine, b ut not risperidone or haloperidol, significantly attenuated the expression of Fos-like protein in the retrosplenial cortex induced by dizocilpine (0.5 mg/kg, s.c.) in a dose-dependent manner. The marked expression of c-fos mR NA in the rat retrosplenial cortex induced by the administration of dizocil pine (0.5 mg/kg, s.c.) was significantly attenuated by pretreatment (15 min ) with clozapine (10 mg/kg) or olanzapine (10 mg/kg), but not risperidone ( 10 mg/kg) or haloperidol (10 mg/kg). The present results suggest that pharm acologically relevant doses of clozapine or olanzapine, but not risperidone or haloperidol, block the neuropathological changes and the expression of Fos-like protein and c-Sos mRNA in the rat retrosplenial cortex elicited by the administration of dizocilpine. It is possible that the blockade of diz ocilpine-induced neuropathological changes by clozapine and olanzapine may be related to the unique antipsychotic actions of these drugs in schizophre nic patients, although this remains to be verified. (C) 2000 Elsevier Scien ce B.V. All rights reserved.