In order to investigate the biochemical mechanisms responsible for glutamate-induced cell death, we have tested the effect of this excitatory amino acid on the growth and survival of several cell lines of neural origin. Most of the cell lines studied were insensitive to glutamate, but we observed in PC12 cells that addition of glutamate (1-10 mmol/l) led to a dose-dependent cell damage (70% of cell lysis at 10 mmol/l as estimated by lactate dehydrogenase release). This effect which was not due to an inhibition of cell proliferation was only obvious after 8-10 h of incubation and required the continuous presence of glutamate for at least 4-6 h, to become apparent. Studies of the cytotoxic effect of several glutamate analogues showed that neither N-methyl-D-aspartate nor kainate, ibotenate, trans(+/-) 1-amino 1,3-cyclopentane dicarboxylic acid or alpha-amino-3-hydroxy-5-methyl isoxazole-4-propionic acid exerted any significant action and that quisqualate only was more potent than glutamate itself. A known antagonist of non-NMDA receptors, the 6,7-dinitroquinoxaline-2,3-dione, was able to significantly decrease the glutamate and quisqualate-induced cell lysis. In addition, we observed that glutamate effect was associated with a significant increase in arachidonate liberation from prelabelled cells.