title: Behavioral effects of N-desmethylclozapine on locomotor activity and sensorimotor gating function in mice-Possible involvement of muscarinic receptors.
abstract: N-desmethylclozapine (NDMC), a major circulating metabolite of the atypical antipsychotic drug, clozapine, and has M(1) muscarinic receptor partial agonistic property. The purpose of the present study was to examine whether in vivo behavioral effects of NDMC were elicited through the activation of muscarinic receptors. Both a non-selective muscarinic receptor agonist, oxotremorine (0.01-0.1mg/kg), and an M(1) and M(4) muscarinic receptor agonist, xanomeline (0.3-3mg/kg), decreased exploratory locomotor activity in mice. This effect was significantly antagonized by a non-selective muscarinic receptor antagonist, scopolamine, at a dose of 0.3mg/kg without affecting exploratory locomotor activity by itself. NDMC (3-30mg/kg) also decreased exploratory locomotor activity in a dose-dependent manner, and the reduced locomotor activity was significantly antagonized by scopolamine at doses of 0.1 and 0.3mg/kg. These results suggested that NDMC might decrease exploratory locomotor activity at least partly through the activation muscarinic receptors in vivo. NDMC (10-30mg/kg) and clozapine (0.3-1mg/kg) dose-dependently increased prepulse inhibition (PPI) in DBA/2J mice, as did xanomeline (1-3mg/kg). Scopolamine at a dose of 0.3mg/kg without altering PPI by itself significantly antagonized the increase of PPI caused by NDMC (30mg/kg), xanomeline (3mg/kg), and oxotremorine (0.06mg/kg). These findings suggest that the activation of muscarinic receptors may be at least partly responsible for exerting the antipsychotic-like effects of both NDMC and xanomeline in an animal model for 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: Hirohiko
authors.initials: H
authors.lastname: Hikichi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ohta
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D018721:Muscarinic Agonists / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects; D010095:Oxotremorine / Q000494:pharmacology; D011601:Psychophysics; D011725:Pyridines / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012601:Scopolamine / Q000494:pharmacology; D055139:Sensory Gating / Q000187:drug effects*; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D018721:Muscarinic Agonists; D011725:Pyridines; D011976:Receptors, Muscarinic; D013830:Thiadiazoles; C058272:norclozapine; D010095:Oxotremorine; C075257:xanomeline; D012601:Scopolamine; D003024:Clozapine