title: The novel 5-HT1A receptor agonist, NLX-112 reduces l-DOPA-induced abnormal involuntary movements in rat: A chronic administration study with microdialysis measurements.
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.
authors.affiliation: Neurolixis Inc., 34145 Pacific Coast Highway #504, Dana Point, CA 92629, USA. Electronic address: amccrear@its.jnj.com.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: McCreary
authors.affiliation: Neurolixis Inc., 34145 Pacific Coast Highway #504, Dana Point, CA 92629, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Varney
authors.affiliation: Neurolixis Inc., 34145 Pacific Coast Highway #504, Dana Point, CA 92629, USA. Electronic address: anewmantancredi@neurolixis.com.
authors.forename: Adrian
authors.initials: A
authors.lastname: Newman-Tancredi
mesh_terms: D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000494:pharmacology* / Q000633:toxicity; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D018592:Cross-Over Studies; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D007980:Levodopa / Q000633:toxicity*; D008297:Male; D017551:Microdialysis; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018726:Anti-Dyskinesia Agents; D004298:Dopamine; D018698:Glutamic Acid; D007980:Levodopa; D016627:Oxidopamine; D010880:Piperidines; D011725:Pyridines; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D005680:gamma-Aminobutyric Acid; C473959:befiradol
keywords: 5-HT(1A) receptor; 5-HT1A agonist; Befiradol; NLX-112; Parkinson's disease; l-DOPA-Induced dyskinesia