Excitotoxins and free radicals individually have been implicated in several neurological disorders including those associated with aging. We observed that systemically administered domoic acid enhanced mouse brain superoxide dismutase activity with either an associated decrease or no change in mouse brain lipid peroxidation. These findings reflect a state of adequately compensated oxidative stress induced by excitotoxins. In homogenates containing disrupted cells from various regions of mouse brain, however, kainic acid produced a 2 to 5-fold increase in lipid peroxidation. This suggests that excitotoxins cause lipid peroxidation possibly by acting at intracellular loci which become more accessible following disruption of cells in vitro and by extrapolation, possibly in vivo due to cellular permeability changes during the edematous stage of ischemic and other related neuropathological conditions.