DYNAMIC CHANGES IN STRIATAL DOPAMINE D-2 AND D-3 RECEPTOR PROTEIN ANDMESSENGER-RNA IN RESPONSE TO 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE (MPTP) DENERVATION IN BABOONS

Loss of nigrostriatal neurons leads to striatal dopamine deficiency an d subsequent development of parkinsonism. The effects of this denervat ion on D-2-like receptors in striatum remain unclear. Most studies hav e demonstrated increases in striatal dopamine D-2-like receptors in re sponse to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated denervation, but others have found either decreases or no change in b inding. To clarify the response to denervation, we have investigated t he time-dependent changes in dopamine D-2, D-3, and D-4 receptor prote in and mRNA levels in unilaterally MPTP-lesioned baboons. MPTP (0.4 mg /kg) was infused into one internal carotid artery, producing a contral ateral hemi-parkinsonian syndrome. After MPTP treatment, the animals w ere maintained for 17-480 d and then euthanized. MPTP decreased ipsila teral dopamine content by >90%, which did not change with time. Ipsila teral D-2-like receptor binding in caudate and putamen initially decre ased then increased two- to sevenfold over the first 100 d and returne d to near baseline levels by 480 d. Relative levels of D-2 mRNA were e ssentially unchanged over this period. D-4 mRNA was not detected. In c ontrast, D-3 mRNA increased sixfold by 2 weeks and then decreased. At the peak period of increase in binding sites, all D-2-like receptors w ere in a micromolar affinity agonist-binding state, implying an increa se in uncoupled D-2 but not D-3 receptor protein. Taken together, thes e data suggest that MPTP-induced changes in D-2-like dopamine receptor s are complex and include translational or post-translational mechanis ms.