The complex dopamine-glutamate interactions within the basal ganglia are disrupted by chronic nigrostriatal denervation and standard replacement therapy with levodopa. Acute N-methyl-D-aspartate (NMDA) receptor blockade is able to overcome the changes in dopamine D1- and D2-dependent responses and the progressive shortening in the duration of response induced by long-term exposure to levodopa in 6-hydroxydopamine-lesioned rats. Preliminary results further suggest that NMDA receptor blockade can counteract levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned non-human primates and parkinsonian patients without substantially altering the motor benefit derived from levodopa. These results appear to be in accordance with our 2-deoxyglucose studies in 6-hydroxydopamine-lesioned rats showing that NMDA receptor blockade can attenuate many of the changes in synaptic activity induced by levodopa, particularly in the striatopallidal complex. Taken together, our observations suggest that abnormal glutamate transmission or dysregulation of NMDA receptor-mediated mechanisms contribute to levodopa-induced motor response complications. Additional preclinical and clinical experiments need to be completed with well tolerated glutamate antagonists to determine the full potential of glutamate receptor blockade as a long-term strategy against levodopa-related motor response complications in Parkinson's disease.