N-Desmethylclozapine exerts dual and opposite effects on salivary secretion in the rat.

N-Desmethylclozapine is a major metabolite of the atypical antipsychotic drug clozapine, used in the treatment of therapy-resistant schizophrenia. Patients under clozapine treatment report a troublesome sialorrhea. Recent experiments show clozapine to exert mixed agonist/antagonist actions on salivary secretion in rats. The present study was performed to define the secretory role of N-desmethylclozapine and to compare it with that of its parent compound. N-Desmethylclozapine evoked secretion by acting directly on the muscarinic acetylcholine M1-receptors of 'silent' duct-cannulated parotid and submandibular glands of the anaesthetized rat. In chronic surgically denervated glands, the secretory response was enlarged. The methacholine-evoked secretion, as well as the parasympathetic nerve-evoked secretion, were reduced by N-desmethylclozapine and involved blockade of M3-receptors, while the sympathetic nerve-evoked response was reduced, involving blockade of alpha(1)-adrenergic receptors. Synergistic interactions between N-desmethylclozapine and the beta-adrenergic receptor agonist, isoprenaline, occurred. Compared with clozapine, the excitatory efficacy of N-desmethylclozapine was higher and the inhibitory efficacy was lower (parasympathetic activity) or about the same (sympathetic activity). Theoretically, in humans treated with clozapine, an increase in the N-desmethylclozapine : clozapine ratio would contribute to salivation during the night and at rest, and, furthermore, the magnitude of the reduction in the reflexly elicited secretion is likely to diminish.