Intrastriatal injection of either kainic acid (0.35 micrograms) or ibotenic acid (7.0 micrograms) in the mouse causes a profound and selective degeneration of striatal neurons accompanied by a secondary astrocytic response. The kainate injection (0.35 micrograms) resulted in significant decrements in the striatal levels of phosphocreatine and ATP by 30 min. a progressive reduction in adenosine phosphates between 30 min and 48 h, and a decrease in energy charge; whereas lactate levels increased by 44% at 2 h, glucose levels fell by 56%. Two hours after intrastriatal injection of ibotenic acid (7.0 micrograms) similar alternations in striatal high-energy phosphates and glucose disposition were found. Prior decortication protected against the neurotoxic effects of kainate in the mouse striatum and prevented the alterations in high-energy phosphates at 2 h although lactate levels increased by 212%. These findings in vivo are consistent with the hypothesis that the neurotoxic effects of acidic excitatory amino acids involve a profound activation of energy consumption by affected neurons.