The cytotoxic action of the excitatory amino acids (EAAs) glutamate, N-methyl-D-aspartate (NMDA), quisqualate (QA), kainate (KA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate (AMPA) was studied in cerebral cortical neurons in culture. The pharmacological profile of these actions was characterized using the NMDA selective antagonist D-(-)-2-amino-5-phosphonopentanoate (APV) and the non-NMDA selective antagonists 6,7-dinitroquinoxaline-2,3-dione (DNQX), 2-amino-3[3-(carboxymethoxy)-5-methylisoxazol-4-yl]-propionate (AMOA) and 2-amino-3-[2-(3-hydroxy-5-methylisoxazol-4-yl)methyl-5-methyl-3- oxoisoxazolin-4-yl]propionate (AMNH). The role of intracellular Ca++ homeostasis and cGMP production for development of EAA mediated cytotoxicity was assessed by measurements of changes in [Ca++]i using the fluorescent Ca++ chelator Fluo-3 and in cGMP concentrations using a conventional radioimmune assay. It was found that glutamate toxicity involves both NMDA and non-NMDA receptor activation and that aberrations in Ca++ homeostasis brought about by Ca++ influx and/or liberation of Ca++ from internal stores are important for development of toxicity. The drug dantrolene which prevents release of Ca++ from such stores can prevent toxicity induced by glutamate, NMDA and QA completely but has no effect on KA and AMPA toxicity. Changes in cGMP levels appear to play a role for development of glutamate, NMDA and KA toxicity but does not seem to be involved in that triggered by QA and AMPA.