Extracellular records were made from subthalamic nucleus neurons during microiontophoretic application of drugs and stimulation of the corticosubthalamic nucleus pathway. In 87% of the subthalamic nucleus cells, cortical stimulation induced a powerful excitation, consisting of a burst of 1-7 spikes. This projection must arise from a large area of the cortex since stimulation of nearly all the ipsilateral cortex and the rostral two-thirds of the contralateral cortex was found to influence the activity of subthalamic nucleus neurons. Experiments were undertaken in order to determine the identity of the neurotransmitter involved in the corticosubthalamic nucleus pathway. Glutamic acid diethyl ester reversibly suppressed subthalamic nucleus excitations induced by ipsi- or contralateral cortical stimulation or microiontophoretically applied glutamate. On the same cells, this compound had no effect on acetylcholine-evoked excitation and gamma-aminobutyric acid-evoked inhibition and subthalamic excitation induced by stimulation of the tegmenti pedunculopontine nucleus. Atropine at doses which antagonized the acetylcholine response, flupenthixol at dose which antagonized the dopamine response, and bicuculline at doses which antagonized the gamma-aminobutyric acid response failed to block excitations evoked by cortical stimulation and by glutamate. These experiments excluded a role for acetylcholine, dopamine and gamma-aminobutyric acid in the cortically evoked excitation of subthalamic nucleus cells. Since an amino acid seemed to play a role as neurotransmitter of the corticosubthalamic nucleus pathway, further experiments were designed to confirm these data and to determine the contribution of each amino acid receptor type in the cortical-induced excitation of subthalamic cells. All the subthalamic cells recorded were also excited by microiontophoretically applied N-methyl-D-aspartic, quisqualic and kainic acids. The cortical-evoked activation of subthalamic nucleus neurons was reversibly suppressed by kynurenic acid and cis-2,3-piperidine dicarboxylic acid, two broad-spectrum antagonists of excitatory amino acids, microiontophoretically applied at doses which also blocked excitations induced by N-methyl-D-aspartic, quisqualic and kainic acids. Application of 2-amino-5-phosphonovaleric acid inhibited excitation induced by N-methyl-D-aspartic acid but not those elicited by quisqualic or kainic acid, while glutamate excitation was only slightly affected. This compound had no effect on the cortically evoked excitation of subthalamic nucleus neurons.(ABSTRACT TRUNCATED AT 400 WORDS)