OBJECTIVE Evidence has accumulated suggesting that ischemia-induced neuronal damage may be linked to an extracellular overflow of glutamate. The purpose of this study was to provide new information about the time course of the increase in extracellular glutamate concentration associated with moderate and severe ischemia, and its relationship with electrical changes including anoxic depolarization. METHODS Changes in the extracellular concentration of glutamate were continuously monitored in the rat striatum by microdialysis. Ischemia was induced by four-vessel occlusion for 3 or 5 minutes, and in some cases its severity was increased with a neck tourniquet. The severity of ischemia was assessed by electroencephalogram and direct current potential recording to detect anoxic depolarization. RESULTS In all experiments, the extracellular glutamate concentration began to increase shortly after the onset of ischemia and steadily rose throughout the ischemic period. Increases up to 35.0 mumol/l (2-3 mumol/l baseline; p less than 0.005) were observed when ischemia provoked the rapid occurrence of a large and sustained anoxic depolarization. Relatively smaller but still significant increases (6.9 mumol/l; p less than 0.005) were observed in penumbral conditions (electroencephalogram loss without anoxic depolarization). Glutamate began to be cleared immediately after reperfusion and 90% of released glutamate was cleared within 5 minutes, even when the preceding ischemia had been severe. CONCLUSIONS We propose that the extracellular glutamate concentration may not reach critical levels during short episodes of penumbral ischemia, but this might happen with a longer ischemic period.