title: Clozapine- and olanzapine-induced Fos expression in the rat medial prefrontal cortex is mediated by beta-adrenoceptors.
abstract: The atypical neuroleptics, clozapine and olanzapine, have superior therapeutic efficacy against the negative symptoms of schizophrenia, compared with the typical neuroleptics. Recently, it has been suggested that the ability of clozapine and olanzapine to induce Fos expression in the medial prefrontal cortex (mPFC), contribute to their therapeutic efficacy. However, the mechanisms underlying the neuropharmacological effects of clozapine and olanzapine in the mPFC remain elusive. In the present study, we demonstrate that clozapine- and olanzapine-induced Fos expression in the mPFC are inhibited by propranolol. We also show that clozapine and olanzapine induce Fos expression in the locus coeruleus. These results suggest that clozapine and olanzapine increase noradrenaline release by stimulating noradrenergic neuronal activity in the locus coeruleus and, consequently, increased noradrenaline induce Fos expression in the mPFC via beta-adrenergic receptors. This postulated sequence may be one of mechanisms by which clozapine-like atypical neuroleptics are more effective for the negative symptoms of schizophrenia.
authors.affiliation: Department of Neuropsychiatry, Okayama University Medical School, Shikata-cho Okayama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ohashi
authors.forename: T
authors.initials: T
authors.lastname: Hamamura
authors.forename: Y
authors.initials: Y
authors.lastname: Lee
authors.forename: Y
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: H
authors.initials: H
authors.lastname: Suzuki
authors.forename: S
authors.initials: S
authors.lastname: Kuroda
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001569:Benzodiazepines; D002452:Cell Count / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
chemical_list: D000319:Adrenergic beta-Antagonists; D014150:Antipsychotic Agents; D016760:Proto-Oncogene Proteins c-fos; D011943:Receptors, Adrenergic, beta; D001569:Benzodiazepines; D010890:Pirenzepine; D011433:Propranolol; D003024:Clozapine; D000077152:Olanzapine