HIGH EXTRACELLULAR GLYCINE DOES NOT POTENTIATE N-METHYL-D-ASPARTATE-EVOKED DEPOLARIZATION IN-VIVO

As N-methyl-D-aspartate receptor (NMDA) ionophore complexes have a dis tinct positive, allosteric regulatory site for glycine, it has been pr oposed that elevated extracellular glycine during or after cerebral is chaemia may induce excessive NMDA/glutamate receptor activation and, t hereby, excitotoxicity. To test this hypothesis, we have perfused incr easing concentrations of glycine, either alone or with co-application of NMDA, through a microdialysis probe implanted in the striatum of ha lothane anaesthetized rats. Changes in the extracellular field (DC) po tential indicative of depolarization were recorded precisely at the si te of drug application by an electrode incorporated within the dialysi s fibre. Microdialysis application of up to 1 mM of glycine had no eff ect on the basal DC potential. Above 10 mM, glycine produced concentra tion-dependent depolarizations, but the amplitude of these responses r emained very small (e.g. 0.52 +/- 0.05 mV for 100 mM glycine, n = 10; i.e. around 30-fold smaller than that of a wave of spreading depressio n). Application of 200 mu M NMDA via the microdialysis probe produced consistent short-lasting depolarizations (around 2.5 mV amplitude), bu t these were not potentiated by co-application of up to 100 mM glycine . These data do not support the view that increased extracellular conc entrations of glycine, such as those observed in ischaemia, may be pot entially excitotoxic. Nevertheless, as occupation of the glycine site coupled to the NMDA-receptor is required for NMDA/glutamate receptor a ctivation, this site remains an attractive target for potential neurop rotective agents.