title: Non-selectivity of amitriptyline for subtypes of brain muscarinic receptors demonstrated in binding and functional assays.
abstract: The characteristics of interaction of amitriptyline, a tricyclic antidepressant, with rat brain muscarinic receptors were assessed using both radioligand binding and functional assays. In competition studies, amitriptyline displaced muscarinic ligand binding from a single high-affinity site in homogenates of various brain regions which have a different distribution of M1 and M2 receptor subtypes. The affinity of amitriptyline for muscarinic receptors was also comparable in all brain regions. Furthermore, amitriptyline identified a single species of muscarinic receptors in intact cells dissociated from the cerebral cortex and in cerebrocortical slices. The non-selectivity of amitriptyline for muscarinic receptor subtypes in these preparations was in contrast to the selectivity exhibited by pirenzepine. This non-selective nature of amitriptyline was also evident in functional assays, since this antidepressant was equipotent at antagonizing M1-mediated increase in phosphoinositide hydrolysis and M2-mediated inhibition of cyclic AMP formation in dissociated cortical cells. Atropine was also equipotent at blocking both responses but was 20- to 30-fold more potent than amitriptyline. These results demonstrate that amitriptyline behaves as a non-selective muscarinic antagonist using both radioligand binding and functional measurements.
authors.affiliation: Department 47U, Abbott Laboratories, North Chicago, IL 60064.
authors.forename: M
authors.initials: M
authors.lastname: McKinney
authors.forename: N H
authors.initials: NH
authors.lastname: Lee
authors.forename: D J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: L
authors.initials: L
authors.lastname: Vella-Rountree
authors.forename: E E
authors.initials: EE
authors.lastname: el-Fakahany
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D004347:Drug Interactions; D006868:Hydrolysis; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D010716:Phosphatidylinositols / Q000378:metabolism; D010890:Pirenzepine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
chemical_list: D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D000639:Amitriptyline; D010890:Pirenzepine; D001285:Atropine; D000242:Cyclic AMP