The effect of ascorbate (1.5 mM)/Fe2+ (7.5 microM)-induced oxidative stress on the release of pre-accumulated [3H]gamma-aminobutyric acid ([3H]GABA) from cultured chick retina cells was studied. Depolarization of control cells with 50 mM K+ increased the release of [3H]GABA by 1.01 +/- 0.16% and 2.5 +/- 0.3% of the total, in the absence and in the presence of Ca2+, respectively. Lipid peroxidation increased the release of [3H]GABA to 2.07 +/- 0.31% and 3.6 +/- 0.39% of the total, in Ca(2+)-free or in Ca(2+)-containing media, respectively. The inhibitor of the GABA carrier, 1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5,6-tetrahydro-3-py ridine- carboxylic acid hydrochloride (NNC-711) blocked almost completely the release of [3H]GABA due to K(+)-depolarization in the absence of Ca2+, but only 65% of the release occurring in the presence of Ca2+ in control and peroxidized cells. Under oxidative stress retina cells release more [3H]GABA than control cells, being the Ca(2+)-independent mechanism, mediated by the reversal of the Na+/GABA carrier, the most affected. MK-801 (1 microM), a non-competitive antagonist of the NMDA receptor-channel complex, blocked by 80% the release of [3H]GABA in peroxidized cells, whereas in control cells the inhibitory effect was of 48%. The non-selective blocker of the non-NMDA glutamate receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), inhibited the release of [3H]GABA by 30% and 70% in control and peroxidized cells, respectively. Glycine (5 microM) stimulated [3H]GABA release evoked by 50 mM K+-depolarization in control but not in peroxidized cells.(ABSTRACT TRUNCATED AT 250 WORDS)