Autoradiographic analysis of N-methyl-D-aspartate receptor binding in monkey brain: Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and levodopa treatment

The anatomic distribution of N-methyl D-aspartate receptors was investigate d in the squirrel monkey brain using quantitative autoradiography with [I-1 25]MK-801 as the radioligand. A heterogeneous distribution of [I-125]MK-801 binding sites was observed, with the most intense expression in the outer cortex, hippocampus, olfactory tubercle, caudate and putamen. High levels w ere also observed in the thalamus, nucleus accumbens and inner cortex, with moderate levels in the claustrum. Relatively low expression levels were de tected in the subthalamic nucleus with no apparent binding in the globus pa llidus and the substantia nigra. Characterization of striatal [I-125]MK-801 binding yielded a B-max of 63.5 fmol/mg tissue and K-d of 0.53 nM in the c audate, with similar values for the putamen. Experiments were subsequently performed to compare striatal [I-125]MK-801 binding in the following four e xperimental groups: (i) control animals injected with saline; (ii) monkeys treated with levodopa; (iii) animals rendered parkinsonian after exposure t o the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; and (iv) dyskinetic monkeys treated with both 1-methyl-4-phenyl-1,2,3,6-tetrahydropy ridine and levodopa. No changes were observed in 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-lesioned animals compared with the saline control group. However, administration of levodopa to either unlesioned or 1-methyl-4-phe nyl-1,2,3,6-tetrahydropyridine-treated monkeys resulted in a significant de crease in [I-125]MK-801 binding in both the caudate and putamen. The data indicate that levodopa exerts a modulatory effect on the striatal glutamatergic system and suggest that a downregulation of N-methyl-D-aspart ate receptors by levodopa, combined with a deficiency in nigrostriatal dopa mine function, may play a role in the development of levodopa induced dyski nesias. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserv ed.