Lesions of the cerebral cortex alter striatal neuronal vulnerability to locally injected kainic acid. Whereas extensive lesions involving the frontal-parietal-occipital cortex are most effective, lesions limited to the frontal or to the dorsal-lateral parietal cortex offer partial protection. The extensive cortical lesions are associated with selective, marked reductions in the presynaptic markers for glutamatergic afferents in striatum. The protective effects of decortication appear between 6 and 24 hours after the lesion and are maintained up to 30 days after decortication. Whereas decortication results in only a transient reduction of specific receptor binding of [3H]kainic acid to striatal membranes, lesion of striatal intrinsic neurons with kainic acid causes a delayed but marked reduction in specific binding of the ligand. Coadministration of L-glutamic acid (1 mumole) with kainic acid (9 nmoles) partially restores the neurotoxic action of kainic acid in the decorticate striatum; GABA, alanine, and proline (1 mumole) are ineffective with regard to restoring kainate's toxicity for striatal GABAergic neurons. These results suggest that afferent input exerts a permissive effect on the neurotoxic action of kainic acid and that neurotoxicity may involve a cooperative interaction between kainic acid at specific receptors on vulnerable neurons and synaptically released endogenous neurotransmitters, in particular L-glutamic acid.