The novel 5-HT1A receptor agonist, NLX-112 reduces l-DOPA-induced abnormal involuntary movements in rat: A chronic administration study with microdialysis measurements

Neuropharmacology. 2016 Jun:105:651-660. doi: 10.1016/j.neuropharm.2016.01.013. Epub 2016 Jan 9.

Abstract

Although l-DOPA alleviates the motor symptoms of Parkinson's disease (PD), it elicits troublesome l-DOPA-induced dyskinesia (LID) in a majority of PD patients after prolonged treatment. This is likely due to conversion of l-DOPA to dopamine as a 'false neurotransmitter' from serotoninergic neurons. The highly selective and efficacious 5-HT1A receptor agonist, NLX-112 (befiradol or F13640) shows potent activity in a rat model of LID (suppression of Abnormal Involuntary Movements, AIMs) but its anti-AIMs effects have not previously been investigated following repeated administration. Acute administration of NLX-112 (0.04 and 0.16 mg/kg i.p.) reversed l-DOPA (6 mg/kg)-induced AIMs in hemiparkinsonian rats with established dyskinesia. The activity of NLX-112 was maintained following repeated daily i.p. administration over 14 days and was accompanied by pronounced decrease of striatal 5-HT extracellular levels, as measured by in vivo microdialysis, indicative of the inhibition of serotonergic activity. A concurrent blunting of l-DOPA-induced surge in dopamine levels on the lesioned side of the brain was observed upon NLX-112 administration and these neurochemical responses were also seen after 14 days of treatment. NLX-112 also suppressed the expression of AIMs in rats that were being primed for dyskinesia by repeated l-DOPA administration. However, when treatment of these rats with NLX-112 was stopped, l-DOPA then induced AIMs with scores that resembled those of control rats. The present study shows that the potent anti-AIMs activity of NLX-112 is maintained upon repeated administration and supports the ongoing clinical development of NLX-112 as a novel antidyskinetic agent for PD patients receiving l-DOPA treatment.

Keywords: 5-HT(1A) receptor; 5-HT1A agonist; Befiradol; NLX-112; Parkinson's disease; l-DOPA-Induced dyskinesia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Dyskinesia Agents / pharmacology*
  • Anti-Dyskinesia Agents / toxicity
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Cross-Over Studies
  • Dopamine / metabolism
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Dyskinesia, Drug-Induced / drug therapy*
  • Dyskinesia, Drug-Induced / metabolism
  • Glutamic Acid / metabolism
  • Levodopa / toxicity*
  • Male
  • Microdialysis
  • Oxidopamine
  • Parkinsonian Disorders / drug therapy
  • Parkinsonian Disorders / metabolism
  • Piperidines / pharmacology*
  • Pyridines / pharmacology*
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Serotonin / metabolism
  • Serotonin 5-HT1 Receptor Agonists / pharmacology*
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Anti-Dyskinesia Agents
  • F 13640
  • Piperidines
  • Pyridines
  • Serotonin 5-HT1 Receptor Agonists
  • Receptor, Serotonin, 5-HT1A
  • Serotonin
  • Glutamic Acid
  • Levodopa
  • gamma-Aminobutyric Acid
  • Oxidopamine
  • Dopamine