Relative potencies of agonists and differential sensitivity to N- ethylmaleimide on muscarinic autoreceptors and postsynaptic receptors in rat hippocampus

MH Richards

Merrell Dow Research Institute, Strasbourg, France.

Relative potencies of nine muscarinic agonists as activators of autoreceptors regulating [3H]acetylcholine release or of postsynaptic receptors, stimulating inositol monophosphate (IP1) formation were determined in rat hippocampal slices. The agonists could be divided into three groups: 1) full agonists at both sites included oxotremorine- M, carbachol and methacholine; 2) full agonists at autoreceptors and partial agonists at receptors coupled to IP1 formation included oxotremorine, arecoline, bethanechol and RS-86; 3) McN-A-343 was a partial agonist at both sites. Arecaidine propargyl ester was a full agonist at autoreceptors but produced a biphasic stimulation of IP1 formation. Comparison of the EC50 values showed that agonists of groups 1 and 3 were more potent at autoreceptors than at IP1-coupled receptors. Group 2 agonists displayed similar potencies at the two types of receptors. N-Ethylmaleimide (NEM) was more active in antagonizing autoreceptors than IP1-coupled receptors in rat hippocampus. Concentration-response curves to carbachol at autoreceptors were shifted to the right in the presence of 10 microM NEM; 30 microM NEM reduced the maximal response. At postsynaptic receptors, higher concentrations of NEM (100 and 120 microM) were required for inhibition of maximum stimulation of IP1 by carbachol. NEM at 160 and 300 microM abolished the stimulation of IP1 induced by carbachol. These observations provide additional evidence that muscarinic autoreceptors differ from the postsynaptic muscarinic receptors that modulate IP1 formation. The similar rank order of agonist potencies between hippocampal autoreceptors and cardiac muscarinic receptors supports the hypothesis that these autoreceptors are of the M2 (cardiac) subtype.

Volume 255, Issue 1, pp. 83-89, 10/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics

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