Glycine enhanced the N-methyl-D-aspartate (NMDA)-stimulated sodium flux in rat hippocampal slides in a concentration-dependent manner. The potentiation by glycine was apparently not competitive to NMDA with a maximal effect of about 50% enhancement at approximately 150 microM glycine. Glycine also reversed the kynurenic acid inhibition of NMDA-stimulated sodium flux, increasing flux two-fold. In the absence of glycine, the kynurenic acid inhibition of NMDA-stimulated sodium flux appeared not competitive to NMDA, with a Schild plot slope of 0.6 +/- 0.1, significantly less than 1 (P less than 0.05). Addition of 100 microM glycine gave a Schild plot slope of 1.0 +/- 0.3, classically defining competitive inhibition. However, the pKb of 4.5 obtained from the x intercept gives an inaccurate estimate of the affinity of kynurenic acid for the NMDA recognition site since glycine is present. Addition of 400 microM glycine resulted in a Schild plot slope of 1.9 +/- 0.2. By varying the concentrations of glycine, we have apparently reproduced a portion of the theoretical set of curves for various ratios of affinities of the antagonist for the agonist recognition site and a second site. These results support a model where glycine modulates NMDA receptor function and where kynurenic acid acts both as a competitive antagonist to NMDA and at a second site from which it is displaced by glycine.

Phenycyclidine (PCP) produces many profound effects in the central nervous system. PCP has numerous behavioral and neurochemical effects such as inhibiting the uptake and facilitating the release of dopamine, serotonin, and norepinephrine. PCP also interacts with sigma, mu opioid, muscarinic, and nicotinic receptors. However, the psychotomimetic effects induced by PCP are believed to be mediated by specific PCP receptors, where PCP binds with greater potency than sigma compounds. Electrophysiological, behavioral, and neuro-chemical evidence strongly suggests that at least some of the many PCP actions result from antagonism of excitatory amino acid-induced responses via PCP receptors. The recent isolation and partial characterization of the alpha and beta endopsychosins and the identification of other endogenous ligands for the PCP and sigma receptors, is another promising area of research in the elucidation of the physiological role of an endogenous PCP and sigma system.

Abstract: The sulfur‐containing amino acids, l‐and d‐cysteate, l‐cysteine, l‐and d‐cysteine sulfinate, l‐and d‐cysteine‐S‐sulfate, l‐cystine, l‐and d‐homocysteate, l‐and d‐homocysteine sulfinate, l‐homocysteine, l‐serine‐O‐sulfate, and taurine were tested in two excitatory amino acid receptor functional assays and in receptor binding assays designed to label specifically the AAl/N‐methyl‐d‐aspartate (NMDA), AA2/quisqualate, and AA3/kainate receptor recognition sites, as well as a CaCla‐dependent l‐2‐amino‐4‐phosphonobutanoate site, and a putative glutamate uptake site. Agonist efficacies were determined by chick retinal excitotoxicity and stimulated sodium efflux from rat brain slices. d‐Homocysteine sulfinate, l‐homocysteate, and l‐serine‐O‐sulfate had affinities most selective for the NMDA binding site, whereas the binding affinities of d‐cysteate, d‐cysteine sulfinate, d‐homocysteate, and l‐homocysteine sulfinate were less selective. However, the correlation of agonist activity sensitive to blockade by d‐2‐amino‐7‐phosphonoheptanoate or d‐2‐amino‐5‐phosphonopentanoate in the functional assays with affinity in the NMDA binding assay (r= 0.87, p < 0.005 and r= 0.98, p < 0.005 for excitotoxicity and sodium efflux, respectively) allows characterization of these sulfur‐containing amino acids as acting at NMDA subclass receptors. l‐Homocysteate, which has been found in the brain, and l‐serine‐O‐sulfate are selective agonists and could serve as endogenous neurotransmitters at the NMDA receptor.