The relationship between intracellular Ca2+ ([Ca 2+]i) regulation and programmed cell death is not well-defined; both increases and decreases in [Ca2+]i have been observed in cells undergoing apoptosis. We determined [Ca 2+]i in cultured murine cortical neurons undergoing apoptosis after exposure to staurosporine or following oxygen-glucose deprivation in the presence of glutamate receptor antagonists. Neuronal [Ca 2+]i was decreased 1-4 h after exposure to staurosporine (30 nM). A [Ca2+]i decrease was also observed 1 h after the end of the oxygen-glucose deprivation period when MK-801 and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) were added to the bathing medium during the deprivation period. A similar decrease in [Ca2+] i produced by reducing extracellular Ca2+ or chelating intracellular Ca2+ was sufficient to induce neuronal apoptosis. Raising [Ca2+]i either by activating voltage-sensitive Ca2+ channels with (-) Bay K8644 or by application of low concentrations of kainate attenuated both staurosporine and oxygen-glucose deprivation-induced apoptosis.