title: Antipsychotic effects of N-desmethylclozapine on sensorimotor gating function in rats--possible involvement of activation of M(1) muscarinic receptors.
abstract: N-desmethylclozapine (NDMC), one of the major metabolites of clozapine, has been demonstrated to exhibit partial agonistic activity at M(1) muscarinic receptors in vitro. Behavioral effects of NDMC were examined to determine whether NDMC contributed to the antipsychotic effects of clozapine via activation of muscarinic receptors. Both NDMC (10-30 mg/kg) and its parent compound clozapine (3-10 mg/kg) antagonized the disruption of prepulse inhibition (PPI) caused by the indirect dopamine agonist methamphetamine (3 mg/kg) in rats. However, NDMC (30 mg/kg) did not increase plasma levels of prolactin in rats. The same dose ranges of NDMC antagonized the disruption of PPI caused by the N-methyl-D-aspartate receptor antagonist ketamine (5 mg/kg) in rats. Furthermore, NDMC in the same dose ranges antagonized the disruption of PPI caused by the muscarinic receptor antagonist scopolamine (0.3 mg/kg) in rats. These findings suggest that NDMC has potent antipsychotic effects in animal models to examine sensorimotor gating function, and that NDMC may act through the activation of a muscarinic receptor for the treatment of schizophrenia.
authors.affiliation: Pharmacology, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan. shunsuke.maehara@mochida.co.jp
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Maehara
authors.forename: Akio
authors.initials: A
authors.lastname: Satow
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Hikichi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ohta
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003024:Clozapine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D011388:Prolactin / Q000097:blood / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D012601:Scopolamine / Q000494:pharmacology; D055139:Sensory Gating / Q000187:drug effects*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D043643:Receptor, Muscarinic M1; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; C058272:norclozapine; D007649:Ketamine; D011388:Prolactin; D012601:Scopolamine; D003024:Clozapine