The 5‐HT2A/2C inverse agonist nelotanserin alleviates L‐DOPA‐induced dyskinesia in the MPTP‐lesioned marmoset

Nelotanserin is a serotonin 2A and 2C (5‐HT2A/2C) inverse agonist that was previously tested in the clinic for rapid‐eye movement sleep behaviour disorder and psychosis in patients with Parkinson's disease (PD) dementia. Its effect on L‐3,4‐dihydroxyphenylalanine (L‐DOPA)‐induced dyskinesia has however not been investigated. As 5‐HT2A antagonism/inverse agonism is a validated approach to alleviate dyskinesia, we undertook the current study to evaluate the anti‐dyskinetic potential of nelotanserin in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned marmoset. Parkinsonism was induced in six common marmosets (Callithrix jacchus, three females and three males) that were then chronically treated with L‐DOPA to induce dyskinesia. On experimental days, they were administered L‐DOPA in combination with vehicle or nelotanserin (0.1, 0.3 and 1 mg/kg) subcutaneously, in a randomised fashion. Dyskinesia and parkinsonism were rated post hoc by a blinded observer. In comparison to vehicle, the addition of nelotanserin 0.3 and 1 mg/kg to L‐DOPA diminished peak dose dyskinesia by 47% (P