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.
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