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.
Ekström
Jörgen
J
Division of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden. jorgen.ekstrom@pharm.gu.se
Godoy
Tania
T
Riva
Alessandro
A
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003024:Clozapine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003714:Denervation; D004357:Drug Synergism; D005260:Female; D007545:Isoproterenol / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology*; D010306:Parotid Gland / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000819:agonists*; D012463:Saliva / Q000378:metabolism; D012472:Salivation / Q000187:drug effects*; D012636:Secretory Rate; D013363:Submandibular Gland / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D000318:Adrenergic beta-Agonists; D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1; C058272:norclozapine; D003024:Clozapine; D007545:Isoproterenol