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Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of L-DOPA-induced dyskinesia.

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Author

  • Ana Munoz
  • Qin Li
  • Fabrizio Gardoni
  • Elena Marcello
  • Chuan Qin
  • Thomas Carlsson
  • Deniz Kirik
  • Monica Di Luca
  • Anders Björklund
  • Erwan Bezard
  • Manolo Carta
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Summary, in English

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-HT(1A) and 5-HT(1B) agonists could reduce l-DOPA-induced dyskinesia. In the present study, we have investigated the efficacy of 5-HT(1A) and 5-HT(1B) 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-HT(1A) and 5-HT(1B) 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-HT(1) 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-HT(1A) and 5-HT(1B) agonists, particularly in combination, in dyskinetic l-DOPA-treated Parkinson's disease patients.

Publishing year

2008

Language

English

Pages

3380-3394

Publication/Series

Brain

Volume

131

Document type

Journal article

Publisher

Oxford University Press

Topic

  • Neurology

Keywords

  • L-DOPA
  • Dyskinesia
  • Serotonin agonists
  • Parkinson's disease
  • MPTP
  • monkeys

Status

Published

Research group

  • Neurobiology
  • Brain Repair and Imaging in Neural Systems (BRAINS)

ISBN/ISSN/Other

  • ISSN: 1460-2156