Abstract
Levodopa dose and severity of Parkinson's disease (PD) are recognized risk factors for levodopa-induced dyskinesia (LID) in humans. The purpose of the present study was to evaluate the ability of these variables to predict severity of LID in a rat model of PD. Varied concentrations of 6-hydroxy-dopamine were injected into the midbrain to produce wide ranges of dopamine depletion in striatum. Three weeks later, rats were given daily injections of levodopa (2–10 mg/kg i.p.) plus benserazide (12.5 mg/kg i.p.) for 15 days. Abnormal involuntary movements (AIMs) were measured for limb, axial, orolingual, and rotatory movements. Dose-response analysis for total AIM scores yielded a levodopa ED50 value of 3.2 mg/kg on treatment day 15. There were strong interrelated correlations between individual AIM categories (ρ > 0.7) and for each AIM category in regard to total AIM score (ρ > 0.7). In rats that received levodopa doses that were greater than the ED50, rates of amphetamine-induced rotation were significantly correlated with total AIM scores (ρ = 0.413). However, of those rotating >5 times/min, 34% had relatively low AIM scores (<8). Likewise, there was a significant correlation between percentages of tyrosine hydroxylase (TH) loss and total AIM scores (ρ = 0.388). However, in those rats that had >85% TH loss, 30% had AIM scores <8. Our results show that given an adequate dose and magnitude of striatal dopamine depletion, levodopa produces dyskinesia with a continuous spectrum of severity. Although levodopa dose and level of dopamine depletion are significant risk factors for LID, we conclude that other factors must contribute to LID susceptibility.
Footnotes
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This work was supported by National Institutes of Health Grant NS38715 and by the Portland Veterans Affairs Parkinson's Disease Research, Education, and Clinical Center.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.126219.
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ABBREVIATIONS: PD, Parkinson's disease; LID, levodopa-induced dyskinesia; 6-OHDA, 6-hydroxydopamine; AIM, abnormal involuntary movement; SNC, substantia nigra zona compacta; ANOVA, analysis of variance; TH, tyrosine hydroxylase; OD, optical density; MFB, median forebrain bundle; PBS, phosphate-buffered saline; LOWESS, locally weighted least-squares smoothing function.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received May 24, 2007.
- Accepted July 26, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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