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 dise ase therapy. In the present experiments, we investigated the relationship b etween D-3 receptor mRNA, D-3 receptor sites and the dopamine transporter i n monkey basal ganglia by comparing their distribution in the brain of cont rol and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys (Samirai sciureus). Tn control monkeys, D-3 receptor mRNA appears to be wi dely expressed throughout the brain, with a distribution similar to that ob served in both man and rodent. D-3 receptors are present in areas which exp ress 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 admini stration, which selectively destroys the nigrostriatal system, resulted in a 70 to 99% depletion of the dopamine transporter in the basal ganglia. Aut oradiographic analysis showed that after MPTP treatment there was a signifi cant decline in D-3 receptors in the caudate, but not putamen, globus palli dus, substantia nigra or other dopaminergic regions. D-3 receptor mRNA expr ession was not changed in any region after nigrostriatal lesioning. Two wee ks of L-3,4-dihydroxyphenylalanine (levodopa, L-DOPA) treatment, which alle viated 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 th e caudate after nigrostriatal degeneration, which is reversed by L-DOPA tre atment. Since the majority of dopaminergic nerve terminals were destroyed a fter MPTP lesioning, the reversal in D-3 receptors after L-DOPA treatment m ay represent an increase in caudate postsynaptic receptors, which could con ceivably contribute to an imbalance in striatal circuitry and the developme nt of dyskinesias. (C) 2000 IBRO. Published by Elsevier Science Ltd, All ri ghts reserved.