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Enhancement of glycine release from human brain cortex synaptosomes by acetylcholine acting at M4 muscarinic receptors.

C. Russo,M. Marchi,G. C. Andrioli,P. Cavazzani,Maurizio Raiteri

Published 1993 in Journal of Pharmacology and Experimental Therapeutics

ABSTRACT

Synaptosomes prepared from fresh specimens of human cerebral cortex were labeled with [3H]glycine ([3H]Gly) and distributed in parallel superfusion chambers. Exposure to 15 mM KCl evoked a tritium overflow which was largely prevented by 10 mM Mg++, suggesting a consistent component of Ca(++)-dependent [3H]Gly release. Acetylcholine (ACh; 1-100 microM), added during K(+)-depolarization, increased the release of tritium in a concentration-dependent manner (maximal effect, 60%; EC50 = 7 microM). Oxotremorine (1-100 microM) mimicked ACh. The effect of 10 microM ACh was insensitive to the nicotinic antagonist mecamylamine (100 microM), but it was blocked by the muscarinic antagonist atropine (0.1 microM). Three muscarinic receptor antagonists, pirenzepine, AF-DX 116 (11-[12-[diethylamino-methyl]-1-piperidinyl]acetyl-5-11-dihydro -6H-pyrido-[2-3-b][1,4]benzodiazepine-6-one) and himbacine, endowed with relative selectivity for various muscarinic receptor subtypes, prevented with differential affinities the effect of 10 microM ACh. Himbacine was the most potent antagonist of ACh, its pA2 (8.34) being 20- or 50-fold higher than that of pirenzepine (7.27) or AF-DX 116 (6.65). It is concluded that: 1) ACh can increase the release of Gly in human cerebral cortex; 2) the interaction occurs through muscarinic receptors which resemble most the M4 subtype; and 3) considering that Gly is required to activate the N-methyl-D-aspartate glutamate receptor, the ACh-evoked Gly release may represent a linkage between cholinergic and glutamatergic transmission, two systems strongly implicated in cognitive processes.

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