Objective: To investigate the effect of the highly-selective serotonin 2A (5-HT2A ) receptor antagonist EMD-281,014 at alleviating L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia in the 6-hydroxydopamine (6-OHDA)-lesioned rat.

Background: Chronic administration of L-DOPA, the most effective symptomatic treatment for Parkinson’s disease (PD), leads to motor complications such as dyskinesia in as many as 95% of patients. Previous studies have suggested that antagonising 5-HT2A receptors may alleviate dyskinesia in animal models of PD, but the drugs assessed interacted with targets other than 5-HT2A receptors and, as such, a 5-HT2A-selective mechanism may not be the only factor underlying their effectiveness. Here, we hypothesised that EMD-281,014, a clinically-ready compound that is currently the most selective 5-HT2A antagonist available, may effectively decrease dyskinesia in PD.

Methods: Rats were rendered hemi-parkinsonian by administration of 6-OHDA. They were then primed with L-DOPA to elicit stable and reproducible axial, limbs and oro-lingual (ALO) abnormal involuntary movements (AIMs). On experimental days, rats were administered L-DOPA in combination with EMD-281,014 (vehicle, 0.01, 0.03 and 0.1 mg/kg), after which ALO AIMs were assessed for 1 min, every 20 min, for 180 min. After a 72h washout period, animals were administered an acute challenge of EMD-281,014 in combination with L-DOPA and the degree of parkinsonism was assessed with the cylinder test.

Results: In combination with L-DOPA, EMD-281,014 mildly, but significantly, diminished the amplitude of dyskinesia, when compared to vehicle. Thus, EMD-281,014 (0.01, 0.03 and 0.1 mg/kg) significantly reduced cumulative ALO AIMs amplitude, when compared to vehicle, by 20%, 14% and 13%, respectively (all P < 0.01). EMD-281,014 (0.01 and 0.1 mg/kg) also reduced cumulative axial AIMs amplitude, by 21% and 18% (both P < 0.05), respectively, when compared to vehicle. Lastly, EMD-281,014 (0.01 and 0.1 mg/kg) diminished cumulative limbs AIMs amplitude, by 40% and 20% (both P < 0.05), respectively, when compared to vehicle. Importantly, EMD-281,014 did not hinder the anti-parkinsonian action of L-DOPA.

Conclusions: These results suggest that the highly-selective 5-HT2A antagonist EMD-281,014 is a promising drug to reduce the severity of dyskinesia in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-highly-selective-5-ht2a-receptor-antagonist-emd-281014-alleviates-l-dopa-induced-dyskinesia-in-the-6-ohda-lesioned-rat-model-of-parkinsons-disease/