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Relationship among nigrostriatal denervation, parkinsonism, and dyskinesias in the MPTP primate model.
Mov Disord. 2000 May; 15(3):459-66.MD

Abstract

Presynaptic denervation is likely to play an important role in the pathophysiology of dyskinesias that develop after levodopa administration to patients with Parkinson's disease. In this study, the thresholds of nigrostriatal damage necessary for the occurrence of parkinsonism and levodopa-induced involuntary movements were compared in squirrel monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Animals treated with a regimen of MPTP that caused parkinsonism displayed > or =95% striatal dopamine depletion, 90% reduction of striatal dopamine uptake sites, and 70% nigral neuronal loss. Levodopa administration ameliorated the parkinsonian signs of these monkeys but also induced dyskinesias. A separate group of animals was treated with a milder MPTP regimen that caused 60%-70% striatal dopamine depletion, a 50% decrease in dopamine transporter, and 40% loss of dopaminergic nigral neurons. While these monkeys displayed no behavioral signs of parkinsonism, they all became dyskinetic after levodopa administration. The priming effect of levodopa, that is, the recurrence of dyskinesias in animals previously exposed to the drug, was compared in severely versus mildly lesioned monkeys. When severely injured parkinsonian animals underwent a second cycle of levodopa treatment, they immediately and consistently developed involuntary movements. In contrast, the recurrence of dyskinesias in primed monkeys with a partial nigrostriatal lesion required several levodopa administrations and remained relatively sporadic. The data indicate that moderate nigrostriatal damage which does not induce clinical parkinsonism predisposes to levodopa-induced dyskinesias. Once dyskinesias have been induced, the severity of denervation may enhance the sensitivity to subsequent levodopa exposures.

Authors+Show Affiliations

The Parkinson's Institute, Sunnyvale, California 94089-1605, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10830409

Citation

Di Monte, D A., et al. "Relationship Among Nigrostriatal Denervation, Parkinsonism, and Dyskinesias in the MPTP Primate Model." Movement Disorders : Official Journal of the Movement Disorder Society, vol. 15, no. 3, 2000, pp. 459-66.
Di Monte DA, McCormack A, Petzinger G, et al. Relationship among nigrostriatal denervation, parkinsonism, and dyskinesias in the MPTP primate model. Mov Disord. 2000;15(3):459-66.
Di Monte, D. A., McCormack, A., Petzinger, G., Janson, A. M., Quik, M., & Langston, W. J. (2000). Relationship among nigrostriatal denervation, parkinsonism, and dyskinesias in the MPTP primate model. Movement Disorders : Official Journal of the Movement Disorder Society, 15(3), 459-66.
Di Monte DA, et al. Relationship Among Nigrostriatal Denervation, Parkinsonism, and Dyskinesias in the MPTP Primate Model. Mov Disord. 2000;15(3):459-66. PubMed PMID: 10830409.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Relationship among nigrostriatal denervation, parkinsonism, and dyskinesias in the MPTP primate model. AU - Di Monte,D A, AU - McCormack,A, AU - Petzinger,G, AU - Janson,A M, AU - Quik,M, AU - Langston,W J, PY - 2000/6/1/pubmed PY - 2000/10/7/medline PY - 2000/6/1/entrez SP - 459 EP - 66 JF - Movement disorders : official journal of the Movement Disorder Society JO - Mov Disord VL - 15 IS - 3 N2 - Presynaptic denervation is likely to play an important role in the pathophysiology of dyskinesias that develop after levodopa administration to patients with Parkinson's disease. In this study, the thresholds of nigrostriatal damage necessary for the occurrence of parkinsonism and levodopa-induced involuntary movements were compared in squirrel monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Animals treated with a regimen of MPTP that caused parkinsonism displayed > or =95% striatal dopamine depletion, 90% reduction of striatal dopamine uptake sites, and 70% nigral neuronal loss. Levodopa administration ameliorated the parkinsonian signs of these monkeys but also induced dyskinesias. A separate group of animals was treated with a milder MPTP regimen that caused 60%-70% striatal dopamine depletion, a 50% decrease in dopamine transporter, and 40% loss of dopaminergic nigral neurons. While these monkeys displayed no behavioral signs of parkinsonism, they all became dyskinetic after levodopa administration. The priming effect of levodopa, that is, the recurrence of dyskinesias in animals previously exposed to the drug, was compared in severely versus mildly lesioned monkeys. When severely injured parkinsonian animals underwent a second cycle of levodopa treatment, they immediately and consistently developed involuntary movements. In contrast, the recurrence of dyskinesias in primed monkeys with a partial nigrostriatal lesion required several levodopa administrations and remained relatively sporadic. The data indicate that moderate nigrostriatal damage which does not induce clinical parkinsonism predisposes to levodopa-induced dyskinesias. Once dyskinesias have been induced, the severity of denervation may enhance the sensitivity to subsequent levodopa exposures. SN - 0885-3185 UR - https://www.unboundmedicine.com/medline/citation/10830409/Relationship_among_nigrostriatal_denervation_parkinsonism_and_dyskinesias_in_the_MPTP_primate_model_ L2 - https://doi.org/10.1002/1531-8257(200005)15:3<459::AID-MDS1006>3.0.CO;2-3 DB - PRIME DP - Unbound Medicine ER -