Journal Article

Combined 5-HT<sub>1A</sub> and 5-HT<sub>1B</sub> receptor agonists for the treatment of <span class="smallCaps">l</span>-DOPA-induced dyskinesia

Ana Muñoz, Qin Li, Fabrizio Gardoni, Elena Marcello, Chuan Qin, Thomas Carlsson, Deniz Kirik, Monica Di Luca, Anders Björklund, Erwan Bezard and Manolo Carta

in Brain

Published on behalf of The Guarantors of Brain

Volume 131, issue 12, pages 3380-3394
Published in print December 2008 | ISSN: 0006-8950
Published online October 2008 | e-ISSN: 1460-2156 | DOI:
Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of l-DOPA-induced dyskinesia

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Appearance of dyskinesia is a common problem of long-term l-DOPA treatment in Parkinson's disease patients and represents a major limitation for the pharmacological management of the motor symptoms in advanced disease stages. We have recently demonstrated that dopamine released from serotonin neurons is responsible for l-DOPA-induced dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, raising the possibility that blockade of serotonin neuron activity by combination of 5-HT1A and 5-HT1B agonists could reduce l-DOPA-induced dyskinesia. In the present study, we have investigated the efficacy of 5-HT1A and 5-HT1B agonists to counteract l-DOPA-induced dyskinesia in 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated macaques, the gold standard model of Parkinson's disease. In addition, we have studied the ability of this treatment to prevent development of l-DOPA-induced dyskinesia in 6-OHDA-lesioned rats. The results demonstrate the existence of a potent synergistic effect between 5-HT1A and 5-HT1B agonists in their ability to dampen l-DOPA-induced dyskinesia in the MPTP-treated macaques. Sub-threshold doses of the drugs, which individually produced no effect, were able to reduce the abnormal involuntary movements by up to 80% when administered in combination, without affecting the anti-parkinsonian properties of l-DOPA. Furthermore, chronic administration of low doses of the 5-HT1 agonists in combination was able to prevent development of dyskinesia, and reduce the up-regulation of FosB after daily treatment with l-DOPA in the rat 6-OHDA model. Our results support the importance of a clinical investigation of the effect of 5-HT1A and 5-HT1B agonists, particularly in combination, in dyskinetic l-DOPA-treated Parkinson's disease patients.

Keywords: L-DOPA; Dyskinesia; Parkinson's disease; Serotonin agonists; MPTP monkeys

Journal Article.  10562 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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