Considerable evidence indicates that dopamine may, under certain circumstances, play a role in the mediation of central nervous system tissue damage. Furthermore, recent studies suggest a synergistic role between the neurotoxic effects of excitatory amino acids and dopamine. To address this issue, rats received a unilateral injection of 6-hydroxydopamine or vehicle into the medial forebrain bundle. After recovery (18 days), both groups of animals received an ibotenic acid injection of the ipsilateral striatum. Seven days later the brains were removed and the size of the striatal lesion was assessed histologically and by means of receptor autoradiography. Regional analysis of profound D1 receptor loss was determined using [3H]SCH 23390, and extent of astrocytic proliferation was examined using autoradiography with the peripheral benzodiazepine receptor ligand [3H]R05-4864. Prior interruption of the nigrostriatal pathway (resulting in dopaminergic denervation of the ipsilateral striatum) partially protected this latter structure from subsequent injection of ibotenic acid (the extent of the lesion was reduced by 28%, P less than .05). The findings indicate that endogenous dopamine release may modulate (and intensify) the excitotoxic effects of ibotenic acid.