Reproducible peracute glutamate-induced focal lesions of the normal rat brain using microdialysis

The neurotoxic effect of the excitatory amino acid neurotransmitter glutamate was first demonstrated 20 years ago, but the recent development of potent glutamate antagonist drugs with effects against ischaemic damage in vivo and their introduction in clinical studies has made 'excitotoxicity' a major focus of current interest. Despite this, the factors influencing glutamate neurotoxicity in vivo are poorly understood, and the role of glutamate as a neurotoxin in vivo is contested. By using a microdialysis probe to deliver glutamate to the normal rat cortex, we have devised a reproducible model of peracute 'excitotoxic' damage. We have demonstrated that concentrations of over 20 mM glutamate in the perfusate kill neurons in the intact brain in less than 90 min -20 to 200 times more than that required for toxicity in mixed cell culture. The histological and ultrastructural features of the glutamate lesion are very similar to those of acute ischaemia, although their development is much more rapid after glutamate. True extracellular glutamate concentrations estimated from microdialysis studies (about 4 mM) are not far from our results. The reproducible quantifiable nature of the glutamate lesions in this model make it well suited to study the factors affecting the excitotoxic process in vivo.