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Effect of the selective 5-HT2A receptor antagonist EMD-281,014 on l-DOPA-induced abnormal involuntary movements in the 6-OHDA-lesioned rat

  • Imane Frouni
  • Cynthia Kwan
  • Dominique Bédard
  • Sébastien Belliveau
  • Élodie Bourgeois-Cayer
  • Fleur Gaudette
  • Francis Beaudry
  • Adjia Hamadjida
  • Philippe Huot
Research Article
  • 34 Downloads

Abstract

l-3,4-Dihydroxyphenylalanine (l-DOPA) is the most effective therapy for motor symptoms of Parkinson’s disease (PD); however, with repeated administration, as many as 94% of PD patients develop complications such as l-DOPA-induced dyskinesia. We previously demonstrated that EMD-281,014, a highly selective serotonin 2A (5-HT2A) receptor antagonist, reduces the severity of dyskinesia in the parkinsonian marmoset, without interfering with l-DOPA anti-parkinsonian benefit. Here, we assessed the effects of EMD-281,014 on l-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat. We first determined the pharmacokinetic profile of EMD-281,014, to administer doses leading to clinically relevant plasma levels in the behavioural experiments. Dyskinetic 6-OHDA-lesioned rats were then administered EMD-281,014 (0.01, 0.03 and 0.1 mg/kg) or vehicle in combination with l-DOPA and AIMs severity was evaluated. We also assessed the effect of EMD-281,014 on l-DOPA anti-parkinsonian action with the cylinder test. We found that the addition of EMD-281,014 (0.01, 0.03 and 0.1 mg/kg) to l-DOPA did not reduce AIMs severity (P > 0.05), when compared to vehicle. EMD-281,014 did not compromise l-DOPA anti-parkinsonian action. Our results suggest that the highly selective 5-HT2A receptor antagonist EMD-281,014 is well-tolerated by parkinsonian rats, but does not attenuate l-DOPA-induced AIMs. Our results highlight differences between rodent and primate models of PD when it comes to determining the anti-dyskinetic action of 5-HT2A receptor antagonists.

Keywords

Parkinson’s disease l-DOPA Dyskinesia Pharmacokinetics EMD-281,014 5-HT2A receptor 

Notes

Acknowledgements

PH has research support from Parkinson Canada, Fonds de Recherche Québec—Santé, the Natural Sciences and Engineering Research Council of Canada and the Weston Brain Institute.

Author contributions

(1) Research project: (A) conception, (B) organisation, (C) execution; (2) Manuscript: (A) writing of the first draft, (B) review and critique. Frouni: 1C, 2A, 2B; Kwan: 1C, 2A, 2B; Bourgeois-Cayer: 1C; Belliveau: 1C; Bédard:1C; Gaudette:1C, 2B; Beaudry: 1C, 2B; Hamadjida: 1B; 2A; 2B; Huot: 1A, 1B, 2B.

Compliance with ethical standards

Conflict of interest

There are no conflicts of interest. PH has received speaker and travel fees from UCB.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Neurodegenerative Disease GroupMontreal Neurological InstituteMontrealCanada
  2. 2.Département de pharmacologie et physiologieUniversité de MontréalMontrealCanada
  3. 3.Integrated Program in NeuroscienceMcGill UniversityMontrealCanada
  4. 4.Plateforme de PharmacocinétiqueCentre de Recherche du Centre Hospitalier de l’Université de MontréalMontrealCanada
  5. 5.Groupe de Recherche en Pharmacologie Animale du Québec, Département de Biomédecine Vétérinaire, Faculté de Médecine VétérinaireUniversité de MontréalSaint-HyacintheCanada
  6. 6.Department of NeuroscienceMcGill UniversityMontrealCanada
  7. 7.Division of NeurologyMcGill University Health CentreMontrealCanada

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