We have examined the effect of cortical spreading depression (SD) and anoxic depolarization (AD) on the interstitial concentration changes of amino acids (AA) in the neocortex of anesthetized rats using microdialysis and HPLC. Accompanying SD alanine increased to126±11%, arginine to116±3%, asparate to160±17%, glutamate to163±9%, glycine to158±21%, serine to125±9%, and taurine to172±15% (mean± 1S.E.M.). The increases lasted for about 1 min. Histidine decreased to74%±4% at 1 min following SD, and returned to normal 4 min later. Cardiac arrest triggered AD after approximately 2 min, immediately followed by changes of interstitial AAs. At 5 min after AD alanine had increased to183±13%, aspartate to3,458±656%, GABA to338±35%, glutamate to1,696±546%, glycine to297±37%, serine to153±12%, and taurine to1721±98% as compared to control values (mean± 1S.E.M.). Histidine decreased to78±2% at 3 min following AD while arginine exhibited insignificant variations around the baseline. The increase of glutamate during SD is consistent with activation of NMDA-receptors as an essential requirement for this reaction. The increase of AAs may also contribute to the sequence of events leading to AD, though the exact mechanism remains unknown. SD is an important pathophysiological mechanism of the ischemic penumbra associated with focal cerebral ischemia, while AD reflects the electrophysiological status of the infarct core. The brief duration of the AA increase during SD may explain survival of cells in the penumbra zone in contrast to the cell death in the infarct center in accord with the excitotoxic hypothesis of ischemic cell death.