While exposure times of several hours or more are needed for AMPA or kainate to induce widespread cortical neurodegeneration, the small subset of cortical neurons that contain high concentrations of the enzyme, NADPH-diaphorase (NADPH-d(+) neurons) were destroyed by brief (15-30 min) exposures. AMPA or kainate-induced degeneration of NADPH-d(+) neurons was decreased by removal of extracellular Ca2+ and increased by augmentation of extracellular Ca2+. More than 90% of NADPH-d(+) neurons exhibited kainate-activated Co2+ uptake, suggesting that they possess Ca(2+)-permeable AMPA/kainate receptor-gated channels. The heightened vulnerability of NADPH-d(+) neurons to AMPA or kainate toxicity may reflect rapid Ca2+ entry through these Ca(2+)-permeable channels.