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Research ArticleNEUROPHARMACOLOGY

Sympathetic Innervation in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Primate Model of Parkinson's Disease

David S. Goldstein, Sheng-Ting Li, Courtney Holmes and Krys Bankiewicz
Journal of Pharmacology and Experimental Therapeutics September 2003, 306 (3) 855-860; DOI: https://doi.org/10.1124/jpet.103.051714
David S. Goldstein
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Sheng-Ting Li
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Courtney Holmes
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Krys Bankiewicz
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Abstract

Cardiac sympathetic denervation occurs commonly in Parkinson's disease. This study explored whether analogous denervation occurs in primates with Parkinsonism from systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 6-[18F]Fluorodopamine positron emission tomographic scanning and plasma levels of catecholamines and their deaminated metabolites were used to assess sympathetic and adrenomedullary function in rhesus monkeys, in the untreated state (n = 3), 2 weeks after a series of four MPTP injections, before establishment of Parkinsonism (acute phase, n = 1); a month later, after four more MPTP doses, associated with severe Parkinsonism (subacute phase, n = 1); or more than 2 years from the last dose (remote phase, n = 3), with persistent severe Parkinsonism. A positive control received i.v. 6-hydroxydopamine 1 week before 6-[18F]fluorodopamine scanning. Acute MPTP treatment increased cardiac 6-[18F]fluorodopamine-derived radioactivity, whereas 6-hydroxydopamine markedly decreased cardiac radioactivity, despite similarly low plasma levels of catecholamines and metabolites after either treatment. Subacutely, plasma catecholamines remained decreased, but now with myocardial 6-[18F]fluorodopamine-derived radioactivity also decreased. Remotely, MPTP-treated monkeys had lower plasma catecholamines and higher myocardial 6-[18F]fluorodopamine-derived radioactivity than did untreated animals. The results indicate that in nonhuman primates, systemic MPTP administration produces multiphasic effects on peripheral catecholamine systems, with nearly complete recovery by 2 years. MPTP- and 6-hydroxydopamine-induced changes differ markedly, probably from ganglionic or preganglionic neurotoxicity with the former and more severe cardiac sympathetic neurotoxicity with the latter. Because of multiphasic sympathetic and adrenomedullary effects, without cardioselective sympathetic denervation at any time, the primate MPTP model does not mimic the changes in peripheral catecholamine systems that characterize the human disease.

Footnotes

  • ↵1 Current address: University of California-San Francisco, San Francisco, CA.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • DOI: 10.1124/jpet.103.051714.

  • ABBREVIATIONS: MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

    • Received March 20, 2003.
    • Accepted April 24, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 306 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 306, Issue 3
1 Sep 2003
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Research ArticleNEUROPHARMACOLOGY

Sympathetic Innervation in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Primate Model of Parkinson's Disease

David S. Goldstein, Sheng-Ting Li, Courtney Holmes and Krys Bankiewicz
Journal of Pharmacology and Experimental Therapeutics September 1, 2003, 306 (3) 855-860; DOI: https://doi.org/10.1124/jpet.103.051714

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Research ArticleNEUROPHARMACOLOGY

Sympathetic Innervation in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Primate Model of Parkinson's Disease

David S. Goldstein, Sheng-Ting Li, Courtney Holmes and Krys Bankiewicz
Journal of Pharmacology and Experimental Therapeutics September 1, 2003, 306 (3) 855-860; DOI: https://doi.org/10.1124/jpet.103.051714
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