Validation of a New Scoring Scale for Behavioral Assessment of L-Dopa-Induced Dyskinesia in the Rat: A New Tool for Early Decision-Making in Drug Development - Université Clermont Auvergne Accéder directement au contenu
Article Dans Une Revue ACS Chemical Neuroscience Année : 2018

Validation of a New Scoring Scale for Behavioral Assessment of L-Dopa-Induced Dyskinesia in the Rat: A New Tool for Early Decision-Making in Drug Development

Résumé

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primate (NHP) has been described as the most translatable model for experimental reproduction of L-dopa-induced dyskinesia (LID). However, from a drug discovery perspective, the risk associated with investment in this type of model is high due to the time and cost. The 6-hydroxydopamine (6-OHDA) rat dyskinesia model is recommended for testing compounds but relies on onerous, and nonstandard behavioral rating scales. We sought to develop a simplified and sensitive method aiming at assessing LID in the rat. The purpose was to validate a reliable tool providing earlier insight into the antidyskinetic potential of compounds in a time/cost-effective manner before further investigation in NHP models. Unilaterally 6-OHDA-lesioned rats were administered L-dopa (20 mg/kg) and benserazide (5 mg/kg) daily for 3 weeks starting 4 weeks postlesion, then coadministered with amantadine (20–30–40 mg/kg). An adapted rating scale was used to score LID frequency and a severity coefficient was applied depending on the features of the observed behavior. A gradual increase (about 3-fold) in LID score was observed over the 3 weeks of L-dopa treatment. The rating scale was sensitive enough to highlight a dose-dependent amantadine-mediated decrease (about 2.2-fold) in LID score. We validated a simplified method, able to reflect different levels of severity in the assessment of LID and, thus, provide a reliable tool for drug discovery.

Domaines

Neurobiologie
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Dates et versions

hal-01693938 , version 1 (13-04-2018)

Identifiants

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Simon Loiodice, Anne-Sophie Denibaud, Wendy Deffains, Magali Alix, Pierre Montagne, et al.. Validation of a New Scoring Scale for Behavioral Assessment of L-Dopa-Induced Dyskinesia in the Rat: A New Tool for Early Decision-Making in Drug Development. ACS Chemical Neuroscience, 2018, 9 (4), pp.762-772. ⟨10.1021/acschemneuro.7b00426⟩. ⟨hal-01693938⟩
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