The aim of the present investigation was to explore if glutamate efflux from human cerebrocortical slices caused by oxygen/glucose deprivation can be controlled by 5-hydroxytryptamine (5-HT). Slices were superfused in aerobic conditions or in conditions simulating moderate ischemic insult (24 min oxygen and glucose deprivation) and the efflux of previously accumulated [3H]D-aspartate and of endogenous glutamate was measured in superfusate fractions. The efflux of both [3H]D-aspartate and endogenous glutamate evoked by ischemia were reduced by at least 50% in the presence of 5-HT (1 microM). Moreover, the 5-HT(1A) receptor agonist 8-OH-DPAT (1 microM) mimicked the 5-HT effect. We conclude that activation of 5-HT receptors of the 5-HT(1A) subtype might help to control glutamate efflux and excitotoxic damage during ischemia in human cerebral cortex and would deserve to be considered in a multipharmacological approach to neuroprotection in brain ischemia.