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

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 (10–30 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.

Research Highlights
► N-desmethylclozapine (NDMC) is a major metabolite of clozapine.
► NDMC antagonized the disruption of PPI caused by methamphetamine and ketamine.
► NDMC also reversed the disruption of PPI caused by scopolamine.
► NDMC may act partly through activation of muscarinic receptors.