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.
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References
Bartoszyk GD, van Amsterdam C, Bottcher H, Seyfried CA (2003) EMD 281014, a new selective serotonin 5-HT2A receptor antagonist. Eur J Pharmacol 473:229–230
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
Connolly BS, Lang AE (2014) Pharmacological treatment of Parkinson disease: a review. JAMA 311:1670–1683
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
Durif F, Debilly B, Galitzky M et al (2004) Clozapine improves dyskinesias in Parkinson disease: a double-blind, placebo-controlled study. Neurology 62:381–388
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 37:86–95
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–S41
French Clozapine Parkinson Study Group (1999) Clozapine in drug-induced psychosis in Parkinson’s disease. The French Clozapine Parkinson Study Group. Lancet 353:2041–2042
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
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
Hamadjida A, Nuara SG, Veyres N et al (2017) The effect of mirtazapine on dopaminergic psychosis and dyskinesia in the parkinsonian marmoset. Psychopharmacology 234:905–911
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
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 81:367–371
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):1355–1360
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 67:300–307
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
Howell DC (2011) Fundamental statistics for the behavioral sciences. Wadsworth Cengage Learning, Belmont
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 25:1399–1408
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
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
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
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
Maertens de Noordhout A, Delwaide PJ (1986) Open pilot trial of ritanserin in parkinsonism. Clin Neuropharmacol 9:480–484
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
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 43:262–270
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 177:111–115
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 340:757–763
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
Roberts C (2006) ACP-103, a 5-HT2A receptor inverse agonist. Curr Opin Investig Drugs 7:653–660
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
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
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
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
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.
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Kwan, C., Frouni, I., Bédard, D. et al. 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. Exp Brain Res 237, 435–442 (2019). https://doi.org/10.1007/s00221-018-5434-9
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DOI: https://doi.org/10.1007/s00221-018-5434-9