Selective interaction of tricyclic antidepressants with a subclass of rat brain cholinergic muscarinic receptors.
Experiments were undertaken to determine whether the anticholinergic actions of tricyclic antidepressants are mediated by a selective interaction with a subclass of muscarinic receptors. To this end, the potencies of these antidepressants to inhibit [3H]-QNB binding to rat brain cerebral cortical membranes was compared to their potencies as antagonists of carbachol-stimulated inositol phosphate accumulation in cerebral cortical slices and carbachol-induced inhibition of GTP-stimulated adenylate cyclase in striatal membranes. Whereas amitriptyline was more potent than pirenzepine, a selective muscarinic M1 receptor antagonist, in competing for [3H]-QNB binding sites and as an antagonist of carbachol-induced inhibition of adenylate cyclase, pirenzepine was substantially more active (ten-fold) than amitriptyline in blocking carbachol-stimulated phosphatidyl inositol turnover. Atropine was more potent than all other agents in these assays, failing to display any significant degree of selectivity. The results suggest that the tricyclic antidepressants, in particular amitriptyline, appear to be selective antagonists for muscarinic receptors associated with adenylate cyclase in striatal membranes. Given the current classification of cholinergic receptors, these findings indicate that the tricyclic antidepressants may be useful for defining the properties of M2 receptors in brain.
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001285:Atropine / Q000494:pharmacology; D001921:Brain / Q000187:drug effects*; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D010276:Parasympatholytics / Q000494:pharmacology; D010890:Pirenzepine / Q000494:pharmacology; D011224:Prazosin / Q000378:metabolism; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism
D000067956:Adenylyl Cyclase Inhibitors; D000929:Antidepressive Agents, Tricyclic; D007295:Inositol Phosphates; D010276:Parasympatholytics; D011942:Receptors, Adrenergic, alpha; D011976:Receptors, Muscarinic; D010890:Pirenzepine; D011813:Quinuclidinyl Benzilate; D001285:Atropine; D011224:Prazosin