EFFECTS OF INCREASED EXTRACELLULAR GLUTAMATE LEVELS ON THE LOCAL-FIELD POTENTIAL IN THE BRAIN OF ANESTHETIZED RATS

1 It is generally considered that glutamate-mediated transmission can be altered from a physiological to neurotoxic action when extracellula r glutamate levels become excessive subsequent to impaired uptake and/ or excessive release. However, high extracellular glutamate does not c onsistently correlate with neuronal dysfunction and death in vivo. The purpose of this study was to examine in situ the local depolarization s, as indicated by negative shifts of the extracellular field (d.c.) p otential, produced by local inhibition of high-affinity glutamate upta ke, with or without co-application of exogenous glutamate, in three br ain regions of anaesthetized rats. 2 Microdialysis probes incorporatin g an electrode were used to apply exogenous glutamate and/or its uptak e inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (L-trans-PDC), and t o monitor the resulting changes in extracellular glutamate and d.c. po tential at the sites of application within the cortex, striatum and hi ppocampus. 3 Perfusion of 1 to 10 mM L-trans-PDC markedly and concentr ation-dependently increased extracellular glutamate levels (by up to 1 700% of basal level in the parietal cortex). Despite their large magni tude, glutamate changes were associated with minor negative shifts of the d.c. potential (<2 mV), which were not suppressed by the N-methyl- D-aspartate (NMDA)-channel blocker, dizocilpine (MK-801, 2 mg kg(-1), i.v.), or the pha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/kainate-receptor antagonist, 6-nitro-7-sulphamoylbenzo(f)quinox aline-2,3-dione (NBQX, 30 mg kg(-1), i.p.). L-trans-PDC had virtually identical concentration-dependent effects on dialysate glutamate in th e hippocampus and striatum, but those induced in the cortex were aroun d 40% larger (P<0.002). In contrast, the associated depolarizations we re around twice as large in the striatum and cortex as in the hippocam pus (P<0.002). Finally, co-application of L-trans-PDC did not enhance the d.c. potential changes evoked by perfusion of 5 or 20 mM glutamate . 4 As the neurotoxic potency of glutamate agonists is considered to b e linked to excessive opening of glutamate-operated ion channels, thes e results challenge the notion that high extracellular glutamate level s may be the key to excitotoxicity in neurological disorders. In parti cular, they do not support the hypothesis that high extracellular glut amate causes the sudden negative shifts of the d.c. potential associat ed with ischaemia (i.e. anoxic depolarization), traumatic brain injury and spreading depression. Impaired uptake and excessive release of gl utamate may well lead to excitotoxicity, but only at the synaptic leve l, not by spreading through the interstitial fluid.