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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.
AuthorsH Iderberg, A C McCreary, M A Varney, M S Kleven, W Koek, L Bardin, R Depoortère, M A Cenci, A Newman-Tancredi
JournalExperimental neurology (Exp Neurol) Vol. 271 Pg. 335-50 (Sep 2015) ISSN: 1090-2430 [Electronic] United States
PMID26037043 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Inc. All rights reserved.
Chemical References
  • Adrenergic Agents
  • Antiparkinson Agents
  • F 13640
  • Neurotransmitter Agents
  • Piperidines
  • Pyridines
  • Serotonin 5-HT1 Receptor Agonists
  • Levodopa
  • Oxidopamine
  • Haloperidol
Topics
  • Adrenergic Agents (toxicity)
  • Animals
  • Antiparkinson Agents (toxicity)
  • Brain (drug effects, metabolism)
  • Catalepsy (chemically induced, drug therapy)
  • Disease Models, Animal
  • Drug Interactions
  • Dyskinesia, Drug-Induced (drug therapy, 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, etiology)
  • Swimming (psychology)
  • Vocalization, Animal (drug effects)

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