Ischemic and traumatic brain injury are likely to involve neuronal injury triggered by glutamate receptor overactivation. Although excitotoxic neuronal injury has been widely studied in the setting of primary culture, the extent to which these in vitro injury paradigms resemble in vivo ischemic injury morphologically has not previously been well studied. We studied glutamate receptor mediated neuronal death by transmission electron microscopy and light microscopy. Morphologic characteristics of neurons injured by 10 min exposure to 500 microM glutamate include rapid swelling of mitochondria and endoplasmic reticulum, and cytoplasmic and nuclear lucency. Both alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and kainic acid caused vacuolation, dilatation of the endoplasmic reticulum, cytoplasmic condensation and random condensation of chromatin with preserved mitochondria. None of these injuries was ameliorated by cycloheximide or actinomycin D; all were significantly lessened by aurintricarboxylic acid. Gel electrophoresis showed no increase in DNA fragmentation over control. The morphologic changes seen with alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and kainate are distinct from the changes induced by glutamate. Excitotoxic injury in this system due to high concentrations of glutamate resembles necrosis while the other agonists produce a different form of cell death which is neither necrosis nor apoptosis.