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.
journal_name
Brain Resjournal_title
Brain researchauthors
Maehara S,Hikichi H,Ohta Hdoi
10.1016/j.brainres.2011.08.056subject
Has Abstractpub_date
2011-10-18 00:00:00pages
111-9eissn
0006-8993issn
1872-6240pii
S0006-8993(11)01583-6journal_volume
1418pub_type
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