title: Effects of antipsychotic drugs on neurotoxicity, expression of fos-like protein and c-fos mRNA in the retrosplenial cortex after administration of dizocilpine.
abstract: 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.
authors.affiliation: Tokyo Laboratories, Pharmaceutical Research Division, Yoshitomi Pharmaceutical Industries, Ltd, Saitama, Iruma, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Fujimura
authors.forename: K
authors.initials: K
authors.lastname: Hashimoto
authors.forename: K
authors.initials: K
authors.lastname: Yamagami
mesh_terms: 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
chemical_list: 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