The effects of chronic intrastriatal and intrahippocampal infusions of endogenous excitatory amino acids were examined on the light microscopic level. Repeated manual injections of either glutamate or aspartate (1.8 mumoles/0.5 mu 1 every 12 hours for 14 days), but not of equimolar GABA, caused neuronal degeneration proximal to the tip of the injection cannula. Nerve cell death was limited to a spherical area with a radius of approximately 0.5 mm. Continuous infusion of these amino acids via osmotic minipumps, at total daily doses identical to those used in the experiments employing manual injections, did not result in lesions in striatum or hippocampus. Attempts using minipump administration of cysteine sulfinate or combinations of glutamate with aspartate, cysteine sulfinate or DL-threo-beta-hydroxyaspartate were equally unsuccessful in producing neuronal cell loss. The efficient re-uptake systems for the endogenous amino acids may suffice to continuously remove large quantities of the infused compounds from vulnerable neuronal sites. It appears, however, that these protective mechanisms can be overcome by extremely high local concentrations of glutamate or aspartate. Possible implications for the pathogenesis of human neurodegenerative disorders are discussed.