EFFECTS OF PHARMACOLOGICAL INHIBITION OF GLUTAMATE-UPTAKE ON ISCHEMIA-INDUCED GLUTAMATE EFFLUX AND ANOXIC DEPOLARIZATION LATENCY

It has been proposed that deficient glutamate uptake, by increasing th e extracellular concentration of this excitatory neurotransmitter, may contribute to the pathophysiology of cerebral ischaemia. This study a imed to examine whether pharmacological inhibition of glutamate uptake altered the kinetics of ischaemia-induced glutamate efflux, and preci pitated anoxic depolarisation. Microdialysis was used for application of the glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylat e (L-trans-PDC), recording of the EEG and extracellular direct current (DC) potential with an electrode within the probe, and continuous mon itoring of changes in extracellular glutamate. L-trans-PDC was applied locally from 8 min prior to cardiac arrest to the end of the recordin g period. L-trans-PDC (2.5 mM) barely altered the time course of postm ortem glutamate efflux in the cortex. Only the maximum rate of efflux during the first exocytotic phase, and the concentration reached at th e end of this phase, appeared slightly increased. L-trans-PDC (5 mM) r educed significantly the delay between EEG silence and anoxic depolari zation in the cerebral cortex (59.2 +/- 9.2 s vs. 79.7 +/- 11.5 s; n = 6), but nor in the striatum and hippocampus. These effects contrast w ith the marked increase in dialysate glutamate that L-trans-PDC produc es in all these three brain regions. Together, these data do not suppo rt the hypothesis that inhibition of glutamate uptake plays a critical role, early in cerebral ischaemia. However, a contribution of reverse d glutamate uptake to the secondary Ca2+-independent phase of ischaemi a-induced glutamate efflux cannot be ruled out.