MK-801 REDUCES UPTAKE AND STIMULATES EFFLUX OF EXCITATORY AMINO-ACIDSVIA MEMBRANE DEPOLARIZATION

MK-801 and related compounds reduce excitotoxic neuronal injury by blo cking N-methyl-D-aspartate (NMDA) receptor-gated ion channels. These a gents also cause neuronal vacuolization and block glutamate-induced as trocyte swelling, effects that may be unrelated to actions at the NMDA receptor. In the present study, high concentrations of MK-801 (100-1, 000 mu M) caused uncompetitive inhibition of glutamate uptake in astro cyte and neuronal cultures and stimulated D-aspartate efflux from astr ocytes. MK-801 (500 mu M) reduced the maximal velocity for glutamate u ptake in astrocytes from 31 to 17 nmol . mg protein(-1). min(-1), wher eas competitive NMDA receptor antagonists did not affect glutamate upt ake. MK-801 also inhibited uptake of gamma-aminobutyric acid (GABA). B ecause both GABA uptake and glutamate uptake are electrogenic, one mec hanism by which MK-801 could inhibit uptake is by membrane depolarizat ion. Whole cell patch-clamp recording confirmed that MK-801 in the ran ge of 100-1,000 mu M caused dose-dependent and reversible depolarizati on. These concentrations are far higher than necessary to block NMDA r eceptors, and the findings suggest that actions at sites other than NM DA receptors could contribute to the effects of high doses of MK-801 i n some experimental and clinical settings.