Repeated intraventricular injection of the excitatory amino acids glutamate and aspartate for one hour produced morphologic changes in the hippocampus that were qualitatively identical to the acute and chronic changes seen in the brains of human epileptics and in experimental animals in which hippocampal seizure activity was induced by kainic acid or electrical stimulation of the perforant path. Light and electron microscopy revealed acute effects of glutamate and aspartate consisting of glial and dendritic swelling and neuronal soma necrosis ("dark cell degeneration"). Electron microscopy showed the focal dendritic swelling induced by glutamate or aspartate to be of the axon-sparing type with presynaptic terminals relatively unaffected. Four weeks after injection, irreversible neuron loss and reactive gliosis had occurred. The inhibitory amino acid gamma-aminobutyric acid caused acute glial swelling similar to that caused by glutamate and aspartate but did not produce neurotoxic effects, indicating that glial swelling may not be causally related to neuronal death but may be the result of amino acid uptake. The excitatory non-amino acid acetylcholine produced no direct, periventricular hippocampal damage or glial swelling but did produce dendritic swelling in the CA3 region innervated by the perforant path, presumably as a result of acetylcholine-induced seizure activity in this pathway. Glutamate and aspartate also caused glial and neuronal changes in other periventricular structures, e.g., septum, hypothalamus, caudate and habenula, as well as in the most dorsal portion of the cerebellum. Dendritic swelling induced by glutamate and aspartate in the cerebellar molecular layer was accompanied by acute necrosis of Purkinje cell somata. These results suggest that seizure-associated brain damage is initiated by excessive endogenous excitatory amino acid receptor activation.