Effect of the selective 5-HT2A receptor antagonist EMD-281,014 on l-DOPA-induced abnormal involuntary movements in the 6-OHDA-lesioned rat
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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.
KeywordsParkinson’s disease l-DOPA Dyskinesia Pharmacokinetics EMD-281,014 5-HT2A receptor
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.
(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.
- Cenci MA, Lundblad M (2007) Ratings of l-DOPA-induced dyskinesia in the unilateral 6-OHDA lesion model of Parkinson’s disease in rats and mice. Curr Protoc Neurosci 41:1–23Google Scholar
- Gaudette F, Hamadjida A, Bédard D, Nuara SG, Beaudry F, Huot P (2017) Development and validation of a high-performance liquid chromatography–tandem mass spectrometry method to quantify LY-354,740 in rat and marmoset plasma. J Chromatogr B 1061–1062:392–398. https://doi.org/10.1016/j.jchromb.2017.07.007 CrossRefGoogle Scholar
- Gaudette F, Hamadjida A, Bedard D et al (2018) Development of a selective and sensitive high-performance liquid chromatography–tandem mass spectrometry assay to support pharmacokinetic studies of LY-487,379 in rat and marmoset. J Chromatogr B Analyt Technol Biomed Life Sci 1093–1094:1–7. https://doi.org/10.1016/j.jchromb.2018.06.036 CrossRefGoogle Scholar
- Hamadjida A, Nuara SG, Bedard D, Gaudette F, Beaudry F, Gourdon JC, Huot P (2018) 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
- Herth MM, Kramer V, Piel M, Palner M, Riss PJ, Knudsen GM, Rosch F (2009) Synthesis and in vitro affinities of various MDL 100907 derivatives as potential 18F-radioligands for 5-HT2A receptor imaging with PET. Bioorg Med Chem 17:2989–3002. https://doi.org/10.1016/j.bmc.2009.03.021 CrossRefGoogle Scholar
- Howell DC (2006) Statistical methods for psychology, 6th edn. Wadsworth Publishing, BelmontGoogle Scholar
- 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
- Huot P, Johnston TH, Winkelmolen L, Fox SH, Brotchie JM (2012a) 5-HT2A receptor levels increase in MPTP-lesioned macaques treated chronically with l-DOPA. Neurobiol Aging 33:194.e195–194.e115Google Scholar
- Huot P, Johnston TH, Winkelmolen L, Fox SH, Brotchie JM (2012b) 5-HT2A receptor levels increase in MPTP-lesioned macaques treated chronically with l-DOPA. Neurobiol Aging 33:194 e195–194 e115. https://doi.org/10.1016/j.neurobiolaging.2010.04.035 Google Scholar
- 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
- Leysen JE, Gommeren W, Van Gompel P, Wynants J, Janssen PF, Laduron PM (1985) Receptor-binding properties in vitro and in vivo of ritanserin: a very potent and long acting serotonin-S2 antagonist. Mol Pharmacol 27:600–611Google Scholar
- 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
- Paxinos G, Watson C (2017) The rat brain in stereotaxic coordinates: compact. Academic Press, New YorkGoogle Scholar
- PD Med Collaborative Group (2014) Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet 384:1196–1205. https://doi.org/10.1016/S0140-6736(14)60683-8 CrossRefGoogle Scholar
- Rowland M, Tozer TN (1995) Clinical pharmacokinetics: concepts and application. Lippincott Williams and Wilkins., PhiladelphiaGoogle Scholar
- 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