Effects of increased extracellular glutamate levels on the local field potential in the brain of anaesthetized rats

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Abstract
It is generally considered that glutamate‐mediated transmission can be altered from a physiological to neurotoxic action when extracellular glutamate levels become excessive subsequent to impaired uptake and/or excessive release. However, high extracellular glutamate does not consistently correlate with neuronal dysfunction and death in vivo. The purpose of this study was to examine in situ the local depolarizations, as indicated by negative shifts of the extracellular field (d.c.) potential, produced by local inhibition of high‐affinity glutamate uptake, with or without co‐application of exogenous glutamate, in three brain regions of anaesthetized rats. Microdialysis probes incorporating an electrode were used to apply exogenous glutamate and/or its uptake inhibitor L‐trans‐pyrrolidine‐2,4‐dicarboxylate (L‐trans‐PDC), and to monitor the resulting changes in extracellular glutamate and d.c. potential at the sites of application within the cortex, striatum and hippocampus. Perfusion of 1 to 10 mM L‐trans‐PDC markedly and concentration‐dependently increased extracellular glutamate levels (by up to 1700% of basal level in the parietal cortex). Despite their large magnitude, glutamate changes were associated with minor negative shifts of the d.c. potential (N‐methyl‐D‐aspartate (NMDA)‐channel blocker, dizocilpine (MK‐801, 2 mg kg−1, i.v.), or the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid (AMPA)/kainate‐receptor antagonist, 6‐nitro‐7‐sulphamoylbenzo(f)quinoxaline‐2,3‐dione (NBQX, 30 mg kg−1, i.p.). L‐trans‐PDC had virtually identical concentration‐dependent effects on dialysate glutamate in the hippocampus and striatum, but those induced in the cortex were around 40% larger (PPtrans‐PDC did not enhance the d.c. potential changes evoked by perfusion of 5 or 20 mM glutamate. As the neurotoxic potency of glutamate agonists is considered to be linked to excessive opening of glutamate‐operated ion channels, these results challenge the notion that high extracellular glutamate levels may be the key to excitotoxicity in neurological disorders. In particular, they do not support the hypothesis that high extracellular glutamate causes the sudden negative shifts of the d.c. potential associated with ischaemia (i.e. anoxic depolarization), traumatic brain injury and spreading depression. Impaired uptake and excessive release of glutamate may well lead to excitotoxicity, but only at the synaptic level, not by spreading through the interstitial fluid. British Journal of Pharmacology (1997) 122, 372–378; doi:10.1038/sj.bjp.0701372