Kainic acid (2-4 days) or ibotenic acid (7-9 days) lesions of the globus pallidus or neostriatum altered the responsiveness of subthalamic nucleus neurons to electrical stimulation of the agranular frontal cortex. Three changes in responsiveness were seen following pallidal lesion: a) An increase in the proportion of responding cells as compared to controls (approximately 90% vs. 60%); b) an increase in the total duration of the evoked response (62.5 ms vs. 28.6 ms); 3) an increase in magnitude of response (9.76 spikes per stimulus vs. 3.24). Both an increase in firing rate (17.94 spikes/s vs. 8.23) and a change to a bursty spontaneous firing pattern were seen. Lesion of the neostriatum had fewer but opposite effects including decreased firing rate (7.21 spikes/s) and decreased total response duration (18.9 ms). These results suggest that the normal tonic inhibition of the subthalamic nucleus by the globus pallidus may play an important role in controlling subthalamic neuronal spontaneous activity and responsiveness. The neostriatum may influence the subthalamic nucleus via the globus pallidus. Globus pallidus lesions may have important consequences on the specificity of cortical control of the subthalamic nucleus and may alter subthalamic influence on basal ganglia output.