NLX-112, a novel 5-HT1A receptor agonist for the treatment of L-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat

Exp Neurol. 2015 Sep;271:335-50. doi: 10.1016/j.expneurol.2015.05.021. Epub 2015 May 30.

Abstract

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.

Keywords: 5-HT1A agonist; 5-HT1A receptor; Befiradol; Mood deficits; NLX-112; Parkinson's disease; l-DOPA-induced dyskinesia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Agents / toxicity
  • Animals
  • Antiparkinson Agents / toxicity*
  • Brain / drug effects*
  • Brain / metabolism
  • Catalepsy / chemically induced
  • Catalepsy / drug therapy
  • Disease Models, Animal
  • Drug Interactions
  • Dyskinesia, Drug-Induced / drug therapy*
  • Dyskinesia, Drug-Induced / etiology
  • Female
  • Haloperidol / toxicity
  • Levodopa / toxicity*
  • Movement / drug effects
  • Neurotransmitter Agents / metabolism
  • Oxidopamine / toxicity
  • Piperidines / therapeutic use*
  • Psychomotor Performance / drug effects
  • Pyridines / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin 5-HT1 Receptor Agonists / therapeutic use*
  • Serotonin Syndrome / drug therapy
  • Serotonin Syndrome / etiology
  • Swimming / psychology
  • Vocalization, Animal / drug effects

Substances

  • Adrenergic Agents
  • Antiparkinson Agents
  • F 13640
  • Neurotransmitter Agents
  • Piperidines
  • Pyridines
  • Serotonin 5-HT1 Receptor Agonists
  • Levodopa
  • Oxidopamine
  • Haloperidol