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-HT1A receptors should thus be an attractive therapeutic strategy, but previous 5-HT1A agonists have yielded disappointing results. Here, we describe the activity of a novel, highly selective and potent
5-HT1A agonist,
NLX-112 (also known as
befiradol or
F13640) in rat models relevant to PD and its associated
affective disorders.
NLX-112 (0.16 mg/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-HT1A 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 (0.01-0.16 mg/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-HT1A agonists upon acute administration. However, upon repeated administration of
NLX-112 (0.63 mg/kg, i.p., twice a day), flat body posture and forepaw treading subsided within 4 days 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.