title: NLX-112, a novel 5-HT1A receptor agonist for the treatment of L-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat.
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.
authors.affiliation: Basal Ganglia Pathophysiology Unit, Dept. of Experimental Medical Sciences, Lund University, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Iderberg
authors.affiliation: Brains On-Line BV, Groningen, The Netherlands.
authors.forename: A C
authors.initials: AC
authors.lastname: McCreary
authors.affiliation: Neurolixis Inc., Dana Point, CA 92629, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Varney
authors.affiliation: Pierre Fabre Laboratories, 81100 Castres, France.
authors.forename: M S
authors.initials: MS
authors.lastname: Kleven
authors.affiliation: Pierre Fabre Laboratories, 81100 Castres, France.
authors.forename: W
authors.initials: W
authors.lastname: Koek
authors.affiliation: Pierre Fabre Laboratories, 81100 Castres, France.
authors.forename: L
authors.initials: L
authors.lastname: Bardin
authors.affiliation: Pierre Fabre Laboratories, 81100 Castres, France.
authors.forename: R
authors.initials: R
authors.lastname: Depoortère
authors.affiliation: Basal Ganglia Pathophysiology Unit, Dept. of Experimental Medical Sciences, Lund University, Sweden.
authors.forename: M A
authors.initials: MA
authors.lastname: Cenci
authors.affiliation: Neurolixis Inc., Dana Point, CA 92629, USA. Electronic address: anewmantancredi@neurolixis.com.
authors.forename: A
authors.initials: A
authors.lastname: Newman-Tancredi
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D004195:Disease Models, Animal; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D006220:Haloperidol / Q000633:toxicity; D007980:Levodopa / Q000633:toxicity*; D009068:Movement / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D010880:Piperidines / Q000627:therapeutic use*; D011597:Psychomotor Performance / Q000187:drug effects; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058825:Serotonin 5-HT1 Receptor Agonists / Q000627:therapeutic use*; D020230:Serotonin Syndrome / Q000188:drug therapy / Q000209:etiology; D013550:Swimming / Q000523:psychology; D014828:Vocalization, Animal / Q000187:drug effects
chemical_list: D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D006220:Haloperidol; D007980:Levodopa; D018377:Neurotransmitter Agents; D016627:Oxidopamine; D010880:Piperidines; D011725:Pyridines; D058825:Serotonin 5-HT1 Receptor Agonists; C473959:befiradol
keywords: 5-HT1A agonist; 5-HT1A receptor; Befiradol; Mood deficits; NLX-112; Parkinson's disease; l-DOPA-induced dyskinesia