LAUSR

ABSTRACT Blockade of serotonin 2A (5‐HT2A) receptors is regarded as an anti‐dyskinetic and anti‐psychotic strategy in Parkinson's disease (PD). However, the 5‐HT2A antagonists tested so far exhibited affinity for other receptors, which might have played a role in their action. EMD‐281,014 is the most selective 5‐HT2A antagonist available, with approximately 2,000‐fold selectivity over serotonin 2C (5‐HT2C) receptors. EMD‐281,014 was previously tested in the clinic and has high translational potential. In the present study, we assessed the effect of EMD‐281,014 on dyskinesia and psychosis in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned common marmoset. We first determined the pharmacokinetic profile of EMD‐281,014 in the marmoset, after which doses leading to clinically‐relevant plasma levels (0.01, 0.03 and 0.1mg/kg) or vehicle were administered to MPTP‐lesioned marmosets, in combination with L‐3,4‐dihydroxyphenylalanine (l‐DOPA). The effects of EMD‐281,014 on dyskinesia, psychosis‐like behaviours (PLBs) and parkinsonism were then evaluated. When added to l‐DOPA, EMD‐281,014 (0.03 and 0.1mg/kg) reduced peak dose dyskinesia, by 41.8% and 54.5% (P<0.05 and P<0.001), when compared to l‐DOPA/vehicle. EMD‐281,014 (0.03 and 0.1mg/kg) also significantly reduced the severity of peak dose PLBs, by 42.5% and 45.9% (P<0.05 and P<0.001), when compared to vehicle. The anti‐dyskinetic and anti‐psychotic effects of EMD‐281,014 were achieved without interfering with l‐DOPA anti‐parkinsonian action. Our results suggest that highly‐selective 5‐HT2A receptor blockade with EMD‐281,014 is an effective way to alleviate both dyskinesia and psychosis in PD, without adversely affecting parkinsonian disability. HIGHLIGHTSEMD‐281,014 is a potent and highly selective 5‐HT2A antagonist.We have determined the pharmacokinetic profile of EMD‐281,014 in the marmoset.EMD‐281,014 reduces l‐DOPA‐induced dyskinesia in the MPTP‐lesioned marmoset.EMD‐281,014 reduces dopaminergic psychosis in the MPTP‐lesioned marmoset.EMD‐281,014 does not hinder the anti‐parkinsonian effect of l‐DOPA.