Expression of D 3 receptor messenger RNA and binding sites in monkey striatum and substantia nigra after nigrostriatal degeneration: effect of levodopa treatment

Abstract

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.