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Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function

Abstract

In monkeys rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), expression of the dopamine D3 receptor was decreased. However, levodopa-induced dyskinesia (LID), similar to the debilitating and pharmacoresistant involuntary movements elicited after long-term treatment with levodopa in patients with Parkinson disease (PD), was associated with overexpression of this receptor. Administration of a D3 receptor–selective partial agonist strongly attenuated levodopa-induced dyskinesia, but left unaffected the therapeutic effect of levodopa. In contrast, attenuation of dyskinesia by D3 receptor antagonists was accompanied by the reappearance of PD-like symptoms. These results indicated that the D3 receptor participated in both dyskinesia and the therapeutic action of levodopa, and that partial agonists may normalize D3 receptor function and correct side effects of levodopa therapy in patients with PD.

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Figure 1: Dyskinesia accompanied by D3 receptor overexpression.
Figure 2: A partial D3 receptor agonist, but not D3 receptor antagonists, reduced LID without affecting the therapeutic effects of levodopa.
Figure 3: The D3 receptor–selective antagonist ST 198.

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Acknowledgements

We thank C. Pilon and C. Imbert for technical assistance, and D. Guilloteau for the gift of [125I](E)-N-(3-iodoprop-2-enyl)-2β- carboxymethyl-3β-(4′-methylphenyl)-nortropane. This work was supported by grants from the Fédération pour la Recherche sur le Cerveau (to P.S. and C.G.), the European Commission (5th Framework Programme to P.S. and H.S.) and the Fondation pour la Recherche Médicale (to E.B. and C.G.).

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Correspondence to Erwan Bézard or Pierre Sokoloff.

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P.S. is named among co-inventors of international patents protecting the D3 receptor and its ligands. P.S. and L.L. are co-inventors in a patent application protecting the in vivo test used to identify a D3 receptor–selective antagonist.

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Bézard, E., Ferry, S., Mach, U. et al. Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function. Nat Med 9, 762–767 (2003). https://doi.org/10.1038/nm875

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