Antipsychotic effects of N-desmethylclozapine on sensorimotor gating function in rats — Possible involvement of activation of M₁ muscarinic receptors

Maehara, Shunsuke; Satow, Akio; Hikichi, Hirohiko; Ohta, Hisashi

Antipsychotic effects of N-desmethylclozapine on sensorimotor gating function in rats — Possible involvement of activation of M₁ muscarinic receptors

2011

Maehara, Shunsuke | Satow, Akio | Hikichi, Hirohiko | Ohta, Hisashi

N-desmethylclozapine (NDMC), one of the major metabolites of clozapine, has been demonstrated to exhibit partial agonistic activity at M₁ 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 (10–30mg/kg) and its parent compound clozapine (3–10mg/kg) antagonized the disruption of prepulse inhibition (PPI) caused by the indirect dopamine agonist methamphetamine (3mg/kg) in rats. However, NDMC (30mg/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 (5mg/kg) in rats. Furthermore, NDMC in the same dose ranges antagonized the disruption of PPI caused by the muscarinic receptor antagonist scopolamine (0.3mg/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.

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