Advertisement

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
  • 50 Downloads

Abstract

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.

Keywords

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

Notes

Acknowledgements

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.

References

  1. Bartoszyk GD, van Amsterdam C, Bottcher H, Seyfried CA (2003) EMD 281014, a new selective serotonin 5-HT2A receptor antagonist. Eur J Pharmacol 473:229–230CrossRefGoogle Scholar
  2. Bhattacharyya S, Raote I, Bhattacharya A, Miledi R, Panicker MM (2006) Activation, internalization, and recycling of the serotonin 2A receptor by dopamine. Proc Natl Acad Sci USA 103:15248–15253.  https://doi.org/10.1073/pnas.0606578103 CrossRefGoogle Scholar
  3. Connolly BS, Lang AE (2014) Pharmacological treatment of Parkinson disease: a review. JAMA 311:1670–1683CrossRefGoogle Scholar
  4. Cummings J, Isaacson S, Mills R et al (2014) Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 383:533–540.  https://doi.org/10.1016/S0140-6736(13)62106-6 CrossRefGoogle Scholar
  5. Durif F, Debilly B, Galitzky M et al (2004) Clozapine improves dyskinesias in Parkinson disease: a double-blind, placebo-controlled study. Neurology 62:381–388CrossRefGoogle Scholar
  6. Fox SH, Visanji N, Reyes G, Huot P, Gomez-Ramirez J, Johnston T, Brotchie JM (2010) Neuropsychiatric behaviors in the MPTP marmoset model of Parkinson’s disease. Can J Neurol Sci 37:86–95CrossRefGoogle Scholar
  7. Fox SH, Katzenschlager R, Lim SY et al (2011) The Movement Disorder Society evidence-based medicine review update: treatments for the motor symptoms of Parkinson’s disease. Mov Disord 26(Suppl 3):S2–S41CrossRefGoogle Scholar
  8. French Clozapine Parkinson Study Group (1999) Clozapine in drug-induced psychosis in Parkinson’s disease. The French Clozapine Parkinson Study Group. Lancet 353:2041–2042CrossRefGoogle Scholar
  9. Frouni I, Kwan C, Bedard D et al (2018) Effect of the selective 5-HT2A receptor antagonist EMD-281,014 on l-DOPA-induced abnormal involuntary movements in the 6-OHDA-lesioned rat. Exp Brain Res.  https://doi.org/10.1007/s00221-018-5390-4 Google Scholar
  10. Goetz CG, Damier P, Hicking C et al (2007) Sarizotan as a treatment for dyskinesias in Parkinson’s disease: a double-blind placebo-controlled trial. Mov Disord 22:179–186.  https://doi.org/10.1002/mds.21226 CrossRefGoogle Scholar
  11. Hamadjida A, Nuara SG, Veyres N et al (2017) The effect of mirtazapine on dopaminergic psychosis and dyskinesia in the parkinsonian marmoset. Psychopharmacology 234:905–911CrossRefGoogle Scholar
  12. Hamadjida A, Nuara SG, Bedard D, Gaudette F, Beaudry F, Gourdon JC, Huot P (2018a) The highly selective 5-HT2A antagonist EMD-281,014 reduces dyskinesia and psychosis in the l-DOPA-treated parkinsonian marmoset. Neuropharmacology 139:61–67.  https://doi.org/10.1016/j.neuropharm.2018.06.038 CrossRefGoogle Scholar
  13. Hamadjida A, Nuara SG, Gourdon JC, Huot P (2018b) The effect of mianserin on the severity of psychosis and dyskinesia in the parkinsonian marmoset. Prog Neuropsychopharmacol Biol Psychiatry 81:367–371CrossRefGoogle Scholar
  14. Hamadjida A, Nuara SG, Gourdon JC, Huot P (2018c) Trazodone alleviates both dyskinesia and psychosis in the parkinsonian marmoset model of Parkinson’s disease. J Neural Transm (Vienna)125(9):1355–1360CrossRefGoogle Scholar
  15. Hely MA, Morris JG, Traficante R, Reid WG, O’Sullivan DJ, Williamson PM (1999) The sydney multicentre study of Parkinson’s disease: progression and mortality at 10 years. J Neurol Neurosurg Psychiatry 67:300–307CrossRefGoogle Scholar
  16. Hely MA, Morris JG, Reid WG, Trafficante R (2005) Sydney Multicenter Study of Parkinson’s disease: non-l-dopa-responsive problems dominate at 15 years. Mov Disord 20:190–199.  https://doi.org/10.1002/mds.20324 CrossRefGoogle Scholar
  17. Howell DC (2011) Fundamental statistics for the behavioral sciences. Wadsworth Cengage Learning, BelmontGoogle Scholar
  18. Huot P, Johnston TH, Darr T et al (2010) Increased 5-HT2A receptors in the temporal cortex of parkinsonian patients with visual hallucinations. Mov Disord 25:1399–1408CrossRefGoogle Scholar
  19. Huot P, Johnston TH, Lewis KD et al (2011) Characterization of 3,4-methylenedioxymethamphetamine (MDMA) enantiomers in vitro and in the MPTP-lesioned primate: R-MDMA reduces severity of dyskinesia, whereas S-MDMA extends duration of ON-time. J Neurosci 31:7190–7198.  https://doi.org/10.1523/JNEUROSCI.1171-11.2011 CrossRefGoogle Scholar
  20. Huot P, Johnston TH, Winkelmolen L, Fox SH, Brotchie JM (2012) 5-HT2A receptor levels increase in MPTP-lesioned macaques treated chronically with l-DOPA. Neurobiol Aging 33:194 e195-115.  https://doi.org/10.1016/j.neurobiolaging.2010.04.035 Google Scholar
  21. Huot P, Johnston TH, Lewis KD et al (2014) UWA-121, a mixed dopamine and serotonin re-uptake inhibitor, enhances l-DOPA anti-parkinsonian action without worsening dyskinesia or psychosis-like behaviours in the MPTP-lesioned common marmoset. Neuropharmacology 82:76–87.  https://doi.org/10.1016/j.neuropharm.2014.01.012 CrossRefGoogle Scholar
  22. Iravani MM, Tayarani-Binazir K, Chu WB, Jackson MJ, Jenner P (2006) In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates, the selective 5-hydroxytryptamine 1a agonist (R)-(+)-8-OHDPAT inhibits levodopa-induced dyskinesia but only with\ increased motor disability. J Pharmacol Exp Ther 319:1225–1234.  https://doi.org/10.1124/jpet.106.110429 CrossRefGoogle Scholar
  23. Maertens de Noordhout A, Delwaide PJ (1986) Open pilot trial of ritanserin in parkinsonism. Clin Neuropharmacol 9:480–484CrossRefGoogle Scholar
  24. Mamo D, Sedman E, Tillner J, Sellers EM, Romach MK, Kapur S (2004) EMD 281014, a specific and potent 5HT2 antagonist in humans: a dose-finding PET study. Psychopharmacology 175:382–388.  https://doi.org/10.1007/s00213-004-1817-7 CrossRefGoogle Scholar
  25. Meco G, Marini S, Linfante I, Modarelli F, Agnoli A (1988) Controlled single-blind crossover study of ritanserin and placebo in l-dopa-induced dyskinesias in Parkinson’s disease. Curr Ther Res 43:262–270Google Scholar
  26. Nash JF, Roth BL, Brodkin JD, Nichols DE, Gudelsky GA (1994) Effect of the R(−) and S(+) isomers of MDA and MDMA on phosphatidyl inositol turnover in cultured cells expressing 5-HT2A or 5-HT2C receptors. Neurosci Lett 177:111–115CrossRefGoogle Scholar
  27. Parkinson Study Group (1999) Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. The Parkinson Study Group. N Engl J Med 340:757–763CrossRefGoogle Scholar
  28. Riahi G, Morissette M, Parent M, Di Paolo T (2011) Brain 5-HT(2A) receptors in MPTP monkeys and levodopa-induced dyskinesias. Eur J Neurosci 33:1823–1831.  https://doi.org/10.1111/j.1460-9568.2011.07675.x CrossRefGoogle Scholar
  29. Roberts C (2006) ACP-103, a 5-HT2A receptor inverse agonist. Curr Opin Investig Drugs 7:653–660Google Scholar
  30. Taylor JL, Bishop C, Ullrich T, Rice KC, Walker PD (2006) Serotonin 2A receptor antagonist treatment reduces dopamine D1 receptor-mediated rotational behavior but not l-DOPA-induced abnormal involuntary movements in the unilateral dopamine-depleted rat. Neuropharmacology 50:761–768.  https://doi.org/10.1016/j.neuropharm.2005.12.004 CrossRefGoogle Scholar
  31. Vanover KE, Weiner DM, Makhay M et al (2006) Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropylo xy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther 317:910–918.  https://doi.org/10.1124/jpet.105.097006 CrossRefGoogle Scholar
  32. Vanover KE, Betz AJ, Weber SM et al (2008) A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model. Pharmacol Biochem Behav 90:540–544.  https://doi.org/10.1016/j.pbb.2008.04.010 CrossRefGoogle Scholar
  33. Veyres N, Hamadjida A, Huot P (2018) Predictive value of parkinsonian primates in pharmacologic studies: a comparison between the macaque, marmoset, and squirrel monkey. J Pharmacol Exp Ther 365:379–397.  https://doi.org/10.1124/jpet.117.247171 CrossRefGoogle Scholar

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

Personalised recommendations