Neuropharmacology 2015-10-01

The highly-selective 5-HT(1A) agonist F15599 reduces L-DOPA-induced dyskinesia without compromising anti-parkinsonian benefits in the MPTP-lesioned macaque.

Philippe Huot, Tom H Johnston, Susan H Fox, Adrian Newman-Tancredi, Jonathan M Brotchie

Index: Neuropharmacology 97 , 306-11, (2015)

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Abstract

L-3,4-dihydroxyphenylalanine (L-DOPA) is the most effective anti-parkinsonian agent available, but upon chronic administration, patients with Parkinson's disease (PD) experience abnormal involuntary movements, dyskinesia. Modulation of serotonin 1A (5-HT1A) receptors is regarded as an effective way to alleviate dyskinesia, yet this approach has been marred by a reduction of the therapeutic effectiveness of L-DOPA. We hypothesised that highly-selective 5-HT1A stimulation might be a way to alleviate dyskinesia without compromising L-DOPA anti-parkinsonian action. F15599 (also known as NLX-101) is a highly-selective 5-HT1A agonist that displays over 1000 × selectivity over off-target receptors. Seven cynomolgus macaques were administered MPTP and developed severe parkinsonism. Following chronic administration of L-DOPA, they developed severe and reproducible dyskinesia. F15599 (0.003, 0.01, 0.03 and 0.1 mg/kg) or vehicle was administered in combination with L-DOPA and its effect on dyskinesia and L-DOPA anti-parkinsonian was assessed. In combination with L-DOPA, F15599 (0.1 mg/kg) reduced the severity of peak-dose dyskinesia, by ≈45% (P < 0.001), compared to L-DOPA alone. F15599 (any dose) had no effect on duration of on-time or motor activity counts compared to L-DOPA alone. F15599 at 0.03 and 0.1 mg/kg significantly reduced duration of on-time with disabling dyskinesia (by ≈49% and ≈71%, P < 0.05 and P < 0.001, respectively). These results suggest that F15599, a highly-selective 5-HT1A receptor agonist, alleviates dyskinesia without exerting a deleterious effect on L-DOPA anti-parkinsonian action.Copyright © 2015 Elsevier Ltd. All rights reserved.