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.
Division of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden. jorgen.ekstrom@pharm.gu.se
Jörgen
J
Ekström
Tania
T
Godoy
Alessandro
A
Riva
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