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Volume 16, Number 23, Issue of December 1, 1996 pp. 7776-7782
Copyright ©1996 Society for Neuroscience

Dynamic Changes in Striatal Dopamine D₂ and D₃ Receptor Protein and mRNA in Response to 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) Denervation in Baboons

Received July 10, 1996; revised Sept. 12, 1996; accepted Sept. 16, 1996.

Richard D. Todd^{1, 2}, Juanita Carl^{1, 5}, Steven Harmon³, Karen L. O'Malley³, and Joel S. Perlmutter^{4, 5}

Departments of ¹ Psychiatry, ² Genetics, ³ Anatomy and Neurobiology, and ⁴ Neurology and Neurosurgery, and ⁵ Mallinkrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110

Loss of nigrostriatal neurons leads to striatal dopamine deficiency and subsequent development of parkinsonism. The effects of this denervation on D₂-like receptors in striatum remain unclear. Most studies have demonstrated increases in striatal dopamine D₂-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 D₂, D₃, and D₄ 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 D₂-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 D₂ mRNA were essentially unchanged over this period. D₄ mRNA was not detected. In contrast, D₃ mRNA increased sixfold by 2 weeks and then decreased. At the peak period of increase in binding sites, all D₂-like receptors were in a micromolar affinity agonist-binding state, implying an increase in uncoupled D₂ but not D₃ receptor protein. Taken together, these data suggest that MPTP-induced changes in D₂-like dopamine receptors are complex and include translational or post-translational mechanisms.

Key words: Parkinson's disease; MPTP; dopamine D₂ receptor; dopamine D₃ receptor; caudate; putamen

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