title: Clozapine-induced salivation: interaction with N-desmethylclozapine and amisulpride in an experimental rat model.
abstract: Many drugs (e.g. amisulpride) have been used to treat troublesome clozapine-induced salivation; however, varying success has been achieved in this respect, probably because, until recently, the salivatory action of clozapine has been largely unexplained. In the rat, clozapine and its main metabolite, N-desmethylclozapine, were found to exert mixed secretory actions: excitatory, through muscarinic acetylcholine M1-receptors giving rise to a long-lasting, low-level flow of saliva; and inhibitory, through muscarinic M3-receptors and α(1) -adrenoceptors reducing the parasympathetically and sympathetically nerve-evoked flow of saliva. The aim of the present study was to define the interactions between clozapine and N-desmethylclozapine, and clozapine and amisulpride, with respect to the excitatory response. Submandibular glands, sensitized by chronic parasympathetic preganglionic denervation, were studied in pentobarbitone-anaesthetized rats. To prevent clozapine from being metabolized to N-desmethylclozapine by hepatic enzymes, the liver was, under terminal anaesthesia, excluded from the circulation. The weak receptor-stimulating clozapine prevented the strong receptor-stimulating N-desmethylclozapine, at specific ratios in humans and in rats, from exerting its full agonistic action. In conclusion, the contribution of N-desmethylclozapine to the clozapine-induced sialorrhoea was, at most, only partly additive. Furthermore, the present experimental set-up failed to demonstrate any anti-salivatory action of amisulpride on the clozapine-induced flow of saliva.
authors: Division of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.
authors: Tania
authors: T
authors: Godoy
authors: Alessandro
authors: A
authors: Riva
authors: Jörgen
authors: J
authors: Ekström
mesh_terms: D000005:Abdomen / Q000601:surgery; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000077582:Amisulpride; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002814:Chorda Tympani Nerve / Q000601:surgery; D003024:Clozapine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D008036:Lingual Nerve / Q000601:surgery; D008102:Liver Circulation / Q000502:physiology; D016210:Methacholine Chloride / Q000494:pharmacology; D023421:Models, Animal; D018721:Muscarinic Agonists / Q000494:pharmacology; D017764:Parasympathectomy; D010646:Phentolamine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000187:drug effects; D043587:Receptor, Muscarinic M3 / Q000187:drug effects; D012463:Saliva / Q000187:drug effects / Q000378:metabolism; D012472:Salivation / Q000187:drug effects*; D013363:Submandibular Gland / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D013469:Sulpiride / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D014150:Antipsychotic Agents; D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D016210:Methacholine Chloride; C058272:norclozapine; D013469:Sulpiride; D000077582:Amisulpride; D011433:Propranolol; D003024:Clozapine; D010646:Phentolamine