Expression of D(3) receptor messenger RNA and binding sites in monkey striatum and substantia nigra after nigrostriatal degeneration: effect of levodopa treatment.
D(3) receptors are prominently localized in the primate caudate-putamen, and D(3) receptor agonist properties may offer an advantage in Parkinson's disease therapy. In the present experiments, we investigated the relationship between D(3) receptor mRNA, D(3) receptor sites and the dopamine transporter in monkey basal ganglia by comparing their distribution in the brain of control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys (Samirai sciureus). In control monkeys, D(3) receptor mRNA appears to be widely expressed throughout the brain, with a distribution similar to that observed in both man and rodent. D(3) receptors are present in areas which express mRNA but also in some which do not, an observation which suggests they may be both pre- and postsynaptic in the monkey brain. Chronic MPTP administration, which selectively destroys the nigrostriatal system, resulted in a 70 to 99% depletion of the dopamine transporter in the basal ganglia. Autoradiographic analysis showed that after MPTP treatment there was a significant decline in D(3) receptors in the caudate, but not putamen, globus pallidus, substantia nigra or other dopaminergic regions. D(3) receptor mRNA expression was not changed in any region after nigrostriatal lesioning. Two weeks of L-3,4-dihydroxyphenylalanine (levodopa, L-DOPA) treatment, which alleviated Parkinsonism but also induced dyskinesias, reversed the MPTP-induced decline in caudate D(3) receptors. These results show that there is a selective decline in D(3) receptors in the caudate after nigrostriatal degeneration, which is reversed by L-DOPA treatment. Since the majority of dopaminergic nerve terminals were destroyed after MPTP lesioning, the reversal in D(3) receptors after L-DOPA treatment may represent an increase in caudate postsynaptic receptors, which could conceivably contribute to an imbalance in striatal circuitry and the development of dyskinesias.
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The Parkinson's Institute, 1170 Morse Avenue, Sunnyvale, CA 94089, USA.mquik@parkinsoninstitue.org
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D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D002421:Caudate Nucleus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D050483:Dopamine Plasma Membrane Transport Proteins; D005260:Female; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D017072:Neostriatum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D009419:Nerve Tissue Proteins; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D050637:Receptors, Dopamine D3; D012453:Saimiri; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine