Dynamic changes in striatal dopamine D-2 and D-3 receptor protein and mRNA 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 and subsequent development of parkinsonism. The effects of this denervation on D-2-like receptors in striatum remain unclear. Most studies have demonstrated increases in striatal dopamine D-2-like receptors in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated denervation, but others have found either decreases or no change in binding. To clarify the response to denervation, we have investigated the time-dependent changes in dopamine D-2, D-3, and D-4 receptor protein and mRNA levels in unilaterally MPTP-lesioned baboons. MPTP (0.4 mg/kg) was infused into one internal carotid artery, producing a contralateral hemi-parkinsonian syndrome. After MPTP treatment, the animals were maintained for 17-480 d and then euthanized. MPTP decreased ipsilateral dopamine content by >90%, which did not change with time. Ipsilateral D-2-like receptor binding in caudate and putamen initially decreased then increased two- to sevenfold over the first 100 d and returned to near baseline levels by 480 d. Relative levels of D-2 mRNA were essentially unchanged over this period. D-4 mRNA was not detected. In contrast, 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 were in a micromolar affinity agonist-binding state, implying an increase in uncoupled D-2 but not D-3 receptor protein. Taken together, these data suggest that MPTP-induced changes in D-2-like dopamine receptors are complex and include translational or post-translational mechanisms.