Glutamate receptors were studied in the brains of controls and Parkinson's disease (PD) patients, of which 10 of 14 developed motor complications (dyskinesias and/or wearing-off) following levodopa therapy. (125)I-RTI binding to the dopamine transporter and dopamine concentrations show comparable nigrostriatal denervation between the subgroups of PD patients. (3)H-Ro 25-6981 binding to the NR1/NR2B NMDA receptor was increased in the putamen of PD patients experiencing motor complications compared to those who did not (+53%) and compared to controls (+18%) whereas binding remained unchanged in the caudate nucleus. (3)H-AMPA binding was increased in the lateral putamen (+23%) of PD patients with motor complications compared to those without whereas it was decreased in the caudate nucleus of the PD patients (-16%) compared to controls. Caudate and putamen (3)H-CGP39653 binding to NR1/NR2A NMDA receptor and NR1 subunit mRNA levels measured by in situ hybridization were unchanged in subgroups of PD patients compared to controls. These findings suggest that glutamate receptor supersensitivity in the putamen plays a role in the development of motor complications (both wearing-Off and dyskinesias) following long-term levodopa therapy in PD.