The current microdialysis study elucidates a functional interaction between the striatal neurotensin NTS1 receptor and the striatal dopamine D2 and N-methyl-d-aspartic acid (NMDA) receptors in the regulation of striatopallidal gamma-aminobutyric acid (GABA) and glutamate levels after an ipsilateral intranigral 6-hydroxydopamine-induced lesion of the ascending dopamine pathways to the striatum. Lateral globus pallidus GABA levels were higher in the lesioned group while no change was observed in striatal GABA and glutamate levels. The 6-hydroxydopamine-induced lesion did not alter the ability of intrastriatal NT (10 nm) to counteract the decrease in pallidal GABA and glutamate levels induced by the dopamine D2-like receptor agonist quinpirole (10 μm). A more pronounced increase in the intrastriatal NMDA- (10 μm) induced increase in pallidal GABA levels was observed in the lesioned group while it attenuated the increase in striatal glutamate levels and amplified the increase in pallidal glutamate levels compared with that observed in the controls. NT enhanced the NMDA-induced increase in pallidal GABA and glutamate and striatal glutamate levels; these effects were counteracted by the NTS1 antagonist SR48692 (100 nm) in both groups. These findings demonstrate an inhibitory striatal dopamine D2 and an excitatory striatal NMDA receptor regulation of striatopallidal GABA transmission in both groups. These actions are modulated by NT via antagonistic NTS1/D2 and facilitatory NTS1/NMDA receptor–receptor interactions, leading to enhanced glutamate drive of the striatopallidal GABA neurons associated with motor inhibition, effects which all are counteracted by SR48692. Thus, NTS1 antagonists in combination with conventional treatments may provide a novel therapeutic strategy in Parkinson’s disease.