APStracts 2:0439C, 1995.

Mk-801 reduces uptake and stimulates efflux of excitatory amino acids via membrane depolarization. Longuemare, Maria C., Edmund C. Keung, Sung Chun, Frank R. Sharp, Pak H. Chan, and Raymond A. Swanson. Graduate Group in Biophysics, Department of Neurology, Department of Medicine, Cardiology Section, and Department of Neurosurgery, University of California and Veterans Affairs Medical Center, San Francisco, CA 94121, and Department of Cardiology, Stanford University, Stanford, CA 94305

APStracts 2:0439C, 1995.

MK-801 and related compounds reduce excitotoxic neuronal injury by blocking NMDA receptor-gated ion channels. These agents also cause neuronal vacuolization and block glutamate-induced astrocyte swelling, effects that may be unrelated to actions at the NMDA receptor. In the present study, high concentrations of MK-801 (100 -1000[mu]M) caused uncompetitive inhibition of glutamate uptake in astrocyte and neuronal cultures and stimulated D-aspartate efflux from astrocytes. MK-801 (500[mu]M) reduced the Vmax for glutamate uptake in astrocytes from 31 to 17 nmol/mg protein/min, while competitive NMDA-R antagonists did not affect glutamate uptake. MK -801 also inhibited uptake of GABA. Since both GABA uptake and glutamate uptake are electrogenic, one mechanism by which MK-801 could inhibit uptake is by membrane depolarization. Whole-cell patch clamp recording confirmed that MK-801 in the range of 100-1000[mu]M caused dose-dependent and reversible depolarization. These concentrations are far higher than necessary to block NMDA receptors, and the findings suggest that actions at sites other than NMDA receptors could contribute to the effects of high doses of MK-801 in some experimental and clinical settings.

Received 31 July 1995; accepted in final form 30 November 1995.
APS Manuscript Number C464-5.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 12 December 95