We examined the effects of Ca(2+)-free medium containing 20 mM Mg2+, a non-selective adenosine receptor antagonist, theophylline, and adenosine transport inhibitors, dipyridamole and nitrobenzylthioinosine, on high K(+)-evoked spreading depression, glutamate, and taurine release from the rat hippocampus using brain microdialysis. High K+ alone perfusion evoked spreading depression and increased glutamate release followed by taurine efflux. Perfusion of Ca(2+)-free medium with high K+ never evoked spreading depression and decreased the high K(+)-evoked taurine release. Perfusion of theophylline (1 mM) increased the occurrence of high K(+)-evoked spreading depression and glutamate release, but did not modify taurine release. In contrast, simultaneous perfusion of dipyridamole (100 microM) and nitrobenzylthioinosine (50 microM) reduced the occurrence of spreading depression and the high K(+)-evoked glutamate release, but enhanced significantly the taurine efflux. These findings suggest that endogenous taurine with adenosine may have neuroprotective actions against high K(+)-evoked glutamate release and spreading depression in the rat hippocampus, in addition to its osmoregulatory action.