Potentiation of response to low doses of levodopa in MPTP-injected monkeys by chemical unilateral subthalamotomy

Laboratory investigation

Vincent A. Jourdain Molecular Endocrinology and Genomic Research Center, CHUQ Research Center (CHUL);
Faculty of Pharmacy, Laval University; and

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Laurent Grégoire Molecular Endocrinology and Genomic Research Center, CHUQ Research Center (CHUL);

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Marc Morissette Molecular Endocrinology and Genomic Research Center, CHUQ Research Center (CHUL);

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Nicolas Morin Molecular Endocrinology and Genomic Research Center, CHUQ Research Center (CHUL);
Faculty of Pharmacy, Laval University; and

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Martin Parent Centre de recherche de l'Institut universitaire en santé mentale de Québec, Quebec City, Quebec, Canada

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Thérèse Di Paolo Molecular Endocrinology and Genomic Research Center, CHUQ Research Center (CHUL);
Faculty of Pharmacy, Laval University; and

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Object

Subthalamotomy is a stereotactic surgery performed in patients with disabling dyskinesias due to Parkinson disease. The authors set out to model this human condition in MPTP monkeys and determine if subthalamotomy allowed a reduction of levodopa for similar benefit.

Methods

The authors performed unilateral subthalamotomy in 4 parkinsonian dyskinetic monkeys by stereotactic injection of ibotenic acid. An optimal dose, defined as the highest dose of levodopa improving parkinsonian motor symptoms while inducing low or no dyskinesias, was established in these animals. Each monkey was scored for the antiparkinsonian and dyskinetic effects of the optimal dose of levodopa, as well as suboptimal and dyskinesia-inducing doses (60% and 140% of the optimal dose, respectively), and these scores were compared with those obtained at baseline before and after subthalamotomy. Bradykinesia was assessed by a prehension task.

Results

Unilateral subthalamotomy had a positive effect on the antiparkinsonian response for all doses of levodopa as well as the baseline. There were no differences in the antiparkinsonian response between the suboptimal dose postsurgery and the optimal dose presurgery. Dyskinesias were increased at the suboptimal and the optimal doses. After surgery, the duration of response to levodopa increased between 20% and 25% in the suboptimal dose, whereas it remained unchanged with higher doses. Bradykinesia was significantly reduced after surgery only at the suboptimal dose.

Conclusions

Subthalamotomy potentiated the response to suboptimal doses of levodopa. Thus, levodopa can be reduced by 40% after surgery for similar beneficial antiparkinsonian response and less dyskinesia than with an optimal dose before surgery.

Abbreviations used in this paper:

LID = levodopa-induced dyskinesia; MPTP =1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NHS = normal horse serum; PBS = phosphate-buffered saline; PD = Parkinson disease; STN = subthalamic nucleus; TH = tyrosine hydroxylase; TRIS = tris(hydroxymethyl)aminomethane; 6-OHDA = 6-hydroxydopamine.
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