We investigated effects of Ebselen, diphenyl diselenide (PhSe)2 and diphenyl ditelluride (PhTe)2 on [3H]glutamate uptake and release by brain synaptosomes. Ebselen after acute exposure inhibited K+-stimulated [3H]glutamate release by brain synaptosomes. (PhSe)2 and (PhTe)2 did not change [3H]glutamate release by brain synaptosomes. Ebselen, (PhSe)2 and (PhTe)2 had no significantly effects on [3H]glutamate uptake after acute exposure. In vitro, Ebselen (100 microM) inhibited [3H]glutamate release and uptake. (PhSe)2 had no significant effect, while (PhTe)2 (100 microM) inhibited [3H]glutamate uptake by brain synaptosomes. In vitro, (PhSe)2, (PhTe)2 and Ebselen caused a significant inhibition of [3H]glutamate uptake by brain synaptic vesicles in vitro. The results demonstrated that organochalcogenides have a rather complex effect on glutamate homeostasis depending on the compound and the schedule of exposition. We propose that the neuroprotective action of Ebselen can be related, in addition to its glutathione peroxidase-like and antilipoperoxidative activity, to a direct interaction with the glutamatergic system by reducing K+-evoked glutamate release.