The cytotoxic action of excitatory amino acids (glutamate, aspartate, NMDA, AMPA, and kainate) was studied in cultured neocortical neurons. It was demonstrated that all amino acids triggered an increase in the intracellular Ca2+ concentration which appeared to be prerequisite for their cytotoxic action. However, while glutamate and NMDA affected both Ca2+ influx and release from intracellular stores, AMPA and kainate preferentially stimulated influx with little (kainate) or no (AMPA) effect on the intracellular store. Using NMDA and non-NMDA receptor selective antagonists it was shown that glutamate cytotoxicity in these neurons is mediated by both receptor subtypes. using the AMPA/kainate selective antagonists AMOA and AMNH it was demonstrated that excitation and neurotoxicity may not be correlated in a simple manner. antagonist and an agonist at AMPA receptors depending on the AMPA concentration.