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 the expression of Fos-like protein and c-fos mRNA in the retrosplenial cortex of female Sprague-Dawley rats induced by the NMDA receptor antagonist dizocilpine. Pretreatment (15 min) with clozapine or olanzapine, but not risperidone or haloperidol, blocked the neuronal vacuolization produced by dizocilpine (0.5 mg/kg, s.c.) in the rat retrosplenial cortex in a dose-dependent manner. Furthermore, pretreatment (15 min) with clozapine or olanzapine, but 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 mRNA in the rat retrosplenial cortex induced by the administration of dizocilpine (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 pharmacologically relevant doses of clozapine or olanzapine, but not risperidone or haloperidol, block the neuropathological changes and the expression of Fos-like protein and c-fos mRNA in the rat retrosplenial cortex elicited by the administration of dizocilpine. It is possible that the blockade of dizocilpine-induced neuropathological changes by clozapine and olanzapine may be related to the unique antipsychotic actions of these drugs in schizophrenic patients, although this remains to be verified.
Fujimura
M
M
Tokyo Laboratories, Pharmaceutical Research Division, Yoshitomi Pharmaceutical Industries, Ltd, Saitama, Iruma, Japan.
Hashimoto
K
K
Yamagami
K
K
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines; D001921:Brain / Q000187:drug effects / Q000473:pathology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism; D009420:Nervous System / Q000187:drug effects* / Q000473:pathology; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000494:pharmacology
D014150:Antipsychotic Agents; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D001569:Benzodiazepines; D010890:Pirenzepine; D016291:Dizocilpine Maleate; D006220:Haloperidol; D018967:Risperidone; D000077152:Olanzapine