Experimental Brain Research

, Volume 237, Issue 2, pp 435–442 | Cite as

5-HT2A blockade for dyskinesia and psychosis in Parkinson’s disease: is there a limit to the efficacy of this approach? A study in the MPTP-lesioned marmoset and a literature mini-review

  • Cynthia Kwan
  • Imane Frouni
  • Dominique Bédard
  • Stephen G. Nuara
  • Jim C. Gourdon
  • Adjia Hamadjida
  • Philippe HuotEmail author
Research Article


Virtually every patient affected by Parkinson’s disease (PD) eventually requires treatment with l-3,4-dihydroxyphenylalanine (l-DOPA), which leads to complications such as dyskinesia and psychosis. Whereas blockade of serotonin 2A (5-HT2A) receptors appears to be an effective way to reduce both dyskinesia and psychosis, whether it has the potential to eliminate the two phenomena remains to be determined. In a previous study, we showed that highly selective 5-HT2A receptor blockade with EMD-281,014, at plasma levels comparable to those achieved in the clinic, reduced dyskinesia and psychosis-like behaviours (PLBs), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to determine whether further increasing the dose would result in greater therapeutic benefit or if maximal effectiveness was achieved at lower doses. Six MPTP-lesioned marmosets with stable dyskinesia and PLBs were administered EMD-281,014 (0.1, 1 and 10 mg/kg) or vehicle in combination with l-DOPA and the effect on dyskinesia, PLBs and parkinsonism was assessed. Administration of EMD-281,014 (0.1, 1 and 10 mg/kg) in combination with l-DOPA resulted in a significant reduction in the severity of dyskinesia, by up to 63%, 64% and 61% (each P < 0.001), when compared to l-DOPA/vehicle. Similarly, the addition of EMD-281,014 (0.1, 1 and 10 mg/kg) to l-DOPA also significantly decreased the severity of PLBs, by up to 54%, 55% and 53% (each P < 0.001), when compared to l-DOPA/vehicle. Our results suggest that there might be a ceiling to the reduction of dyskinesia and psychosis that can be achieved through antagonism of 5-HT2A receptors.


EMD-281,014 Parkinson’s disease Dyskinesia Psychosis MPTP Marmoset 



PH has research support from Parkinson Canada, Fonds de Recherche Québec—Santé, the Natural Sciences and Engineering Research Council of Canada, the Michael J Fox Foundation for Parkinson's Research  and the Weston Brain Institute.

Compliance with ethical standards

Conflict of interest

There are no conflicts of interest. PH has received payments from UCB.


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Copyright information

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

Authors and Affiliations

  • Cynthia Kwan
    • 1
    • 2
  • Imane Frouni
    • 1
    • 3
  • Dominique Bédard
    • 1
  • Stephen G. Nuara
    • 4
  • Jim C. Gourdon
    • 4
  • Adjia Hamadjida
    • 1
    • 2
  • Philippe Huot
    • 1
    • 2
    • 3
    • 5
    • 6
    Email author
  1. 1.Neurodegenerative Disease GroupMontreal Neurological InstituteMontrealCanada
  2. 2.Integrated Program in NeuroscienceMcGill UniversityMontrealCanada
  3. 3.Département de Pharmacologie et PhysiologieUniversité de MontréalMontrealCanada
  4. 4.Comparative Medicine and Animal Resource CentreMcGill UniversityMontrealCanada
  5. 5.Department of NeuroscienceMcGill UniversityMontrealCanada
  6. 6.Division of NeurologyMcGill University Health CentreMontrealCanada

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