Previously we have demonstrated that mature inbred strains of mice differ significantly in their response to kainate-induced cell death. While both C57BL/6 and FVB/N mice exhibit similar seizure activity in response to kainate, only C57BL/6 mice can be characterized as resistant to kainate-induced cell death. To examine further the molecular pharmacological basis for this strain difference in hippocampal sensitivity, we assessed the ability of the ionotropic glutamate receptor agonists, kainic acid (KA), N-methyl-D-aspartate (NMDA), ibotenic acid (IBO), and quinolinic acid (QUIN), to promote excitotoxic damage. We examined seizure-related behavior and subsequent neurotoxicity in C57BL/6 and FVB/N mice following intrahippocampal administration of the kainate receptor agonist, KA, the NMDA receptor agonists NMDA or QUIN, or the NMDA and metabotropic glutamate receptor agonist, IBO. The time course and extent of cell death in mice were evaluated using Nissl and selective silver stains, and Fluoro-Jade, a fluorescent marker for dying neurons. In the present study, FVB/N mice were exquisitely sensitive to injection of KA at all doses, while susceptibility in C57BL/6 mice was dose dependent. In contrast, while hippocampal damage was present in both strains at all doses of QUIN, the extent of cell damage was significantly less in C57BL/6 mice at low doses (30 and 60 mM). Similarly, IBO administration resulted in differences in the extent of cell death when administered at the highest dose (126 mM). No strain-dependent differences in cell loss were observed following NMDA lesions. These results provide further evidence that susceptibility to excitotoxin-induced cell death is highly strain dependent and is kainate and NMDA receptor dependent.