NLX-112, a novel 5-HT<inf>1A</inf> receptor agonist for the treatment of l-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat

l-DOPA is the gold-standard treatment for Parkinson's disease (PD), but induces troublesome dyskinesia after prolonged treatment. This is associated with the 'false neurotransmitter' conversion of l-DOPA to dopamine by serotonin neurons projecting from the raphe to the dorsal striatum. Reducing their activity by targeting pre-synaptic 5-HT<inf>1A</inf> receptors should thus be an attractive therapeutic strategy, but previous 5-HT<inf>1A</inf> agonists have yielded disappointing results. Here, we describe the activity of a novel, highly selective and potent 5-HT<inf>1A</inf> agonist, NLX-112 (also known as befiradol or F13640) in rat models relevant to PD and its associated affective disorders. NLX-112 (0.16mg/kg, i.p.) potently and completely reversed haloperidol-induced catalepsy in intact rats and abolished l-DOPA-induced Abnormal Involuntary Movements (AIMs) in hemiparkinsonian rats, an effect that was reversed by the selective 5-HT<inf>1A</inf> antagonist, WAY100635. In microdialysis experiments, NLX-112 profoundly decreased striatal 5-HT extracellular levels, indicative of inhibition of serotonergic function. NLX-112 also blunted the l-DOPA-induced surge in dopamine levels on the lesioned side of the brain, an action that likely underlies its anti-dyskinetic effects. NLX-112 (0.16. mg/kg, i.p.) robustly induced rotations in hemiparkinsonian rats, suggesting that it has a motor facilitatory effect. Rotations were abolished by WAY100635 and were ipsilateral to the lesioned side, suggesting a predominant stimulation of the dopamine system on the non-lesioned side of the brain. NLX-112 also efficaciously reduced immobility time in the forced swim test (75% reduction at 0.16. mg/kg, i.p.) and eliminated stress-induced ultrasonic vocalization at 0.08. mg/kg, i.p., effects consistent with potential antidepressant- and anxiolytic-like properties. In other tests, NLX-112 (0.01-0.16mg/kg, i.p.) did not impair the ability of l-DOPA to rescue forepaw akinesia in the cylinder test but decreased rotarod performance, probably due to induction of flat body posture and forepaw treading which are typical of 5-HT<inf>1A</inf> agonists upon acute administration. However, upon repeated administration of NLX-112 (0.63mg/kg, i.p., twice a day), flat body posture and forepaw treading subsided within 4days of treatment. Taken together, these observations suggest that NLX-112 could exhibit a novel therapeutic profile, combining robust anti-dyskinetic properties without impairing the therapeutic properties of l-DOPA, and with additional beneficial effects on non-motor (affective) symptoms.