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 investigated in the squirrel monkey brain using quantitative autoradiography with [125I]MK-801 as the radioligand. A heterogeneous distribution of [125I]MK-801 binding sites was observed, with the most intense expression in the outer cortex, hippocampus, olfactory tubercle, caudate and putamen. High levels were also observed in the thalamus, nucleus accumbens and inner cortex, with moderate levels in the claustrum. Relatively low expression levels were detected in the subthalamic nucleus with no apparent binding in the globus pallidus and the substantia nigra. Characterization of striatal [125I]MK-801 binding yielded a B(max) of 63.5 fmol/mg tissue and K(d) of 0.53 nM in the caudate, with similar values for the putamen. Experiments were subsequently performed to compare striatal [125I]MK-801 binding in the following four experimental groups: (i) control animals injected with saline; (ii) monkeys treated with levodopa; (iii) animals rendered parkinsonian after exposure to 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-tetrahydropyridine 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-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys resulted in a significant decrease in [125I]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 down-regulation of N-methyl-D-aspartate receptors by levodopa, combined with a deficiency in nigrostriatal dopamine function, may play a role in the development of levodopa induced dyskinesias.
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The Parkinson's Institute, 1170 Morse Ave., Sunnyvale, CA 94089, USA. lihe@parkinsoninstitute.org
Di Monte
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Langston
J W
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Quik
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D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D001923:Brain Chemistry / Q000187:drug effects*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000378:metabolism / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology; D007457:Iodine Radioisotopes; D007980:Levodopa / Q000494:pharmacology*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism; D011869:Radioligand Assay; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis* / Q000378:metabolism*; D012453:Saimiri
D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; D007457:Iodine Radioisotopes; D016194:Receptors, N-Methyl-D-Aspartate; D007980:Levodopa; D016291:Dizocilpine Maleate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine