A phencyclidine recognition site is associated with N-methyl-D- aspartate inhibition of carbachol-stimulated phosphoinositide hydrolysis in rat cortical slices

RA Gonzales and JM Moerschbaecher

Department of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin 78712.

The effects of N-methyl-D-aspartate (NMDA) on muscarinic receptor- stimulated phosphoinositide (PI) hydrolysis in rat cortical slices were studied. NMDA inhibits carbachol-stimulated PI hydrolysis with an IC50 of 9.8 +/- 1.4 microM and a maximal inhibition of 70% at 100 microM. The inhibitory effect of NMDA is not due to increased metabolism of accumulated inositol phosphates. NMDA inhibition of carbachol- stimulated PI hydrolysis was significantly reduced in the absence of extracellular calcium. Although the inhibitory effect of NMDA is observed in the presence of 1.18 mM Mg2+, the concentration-response curve is slightly shifted to the left (5-fold) in the absence of extracellular Mg2+. Antagonists of NMDA-evoked excitations were effective inhibitors of the NMDA modulation of PI hydrolysis, including the competitive antagonist 2-amino-5-phosphonopentanoic acid and the noncompetitive antagonist MK-801. The rank order of potencies of the antagonists were MK-801 greater than phencyclidine = (-)-cyclazocine greater than ketamine = etoxadrol greater than N-allylnormetazocine greater than 2-amino-5-phosphonopentanoic acid. (+)-MK-801 and (-)- cyclazocine were more potent inhibitors, by 4-5-fold, of the NMDA response than their respective isomers, whereas N-allylnormetazocine isomers were approximately equipotent antagonists. The activity of dexoxadrol against NMDA inhibition of carbachol-stimulated PI hydrolysis could not be determined because of its antimuscarinic effects. The rank order of potencies of antagonists, the stereoselectivity of the isomers of MK-801, cyclazocine, and N- allylnormetazocine, and Mg2+ sensitivity of the NMDA inhibitory response suggest that a phencyclidine binding similar to the one located in the cation channel gated by NMDA receptors is associated with the NMDA receptor that modulates muscarinic-stimulated PI hydrolysis.

Volume 35, Issue 6, pp. 787-794, 06/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics

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