Involvement of the GABA A receptor α subunit in the mode of action of etifoxine

Etifoxine (EFX) is a non-benzodiazepine psychoactive drug which exhibits anxiolytic effects through a dual mechanism, by directly binding to GABA receptors (GABA Rs) and to the mitochondrial 18-kDa translocator protein, resulting in the potentiation of the GABAergic function. The β subunit subtype p...

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Bibliographic Details
Published in:Pharmacological research 2019-07, Vol.145, p.104250
Main Authors: Mattei, César, Taly, Antoine, Soualah, Zineb, Saulais, Ophélie, Henrion, Daniel, Guérineau, Nathalie C, Verleye, Marc, Legros, Christian
Format: Article
Language:English
Subjects:
Animals
Anti-Anxiety Agents - pharmacology
Anti-Anxiety Agents - therapeutic use
Anxiety - drug therapy
Anxiety - metabolism
Anxiety - physiopathology
Female
Locomotion - drug effects
Male
Mice, Inbred BALB C
Mice, Inbred C57BL
Models, Molecular
Oocytes - physiology
Oxazines - pharmacology
Oxazines - therapeutic use
Protein Subunits - genetics
Protein Subunits - metabolism
Psychomotor Performance - drug effects
Receptors, GABA-A - genetics
Receptors, GABA-A - metabolism
Xenopus laevis
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Summary:Etifoxine (EFX) is a non-benzodiazepine psychoactive drug which exhibits anxiolytic effects through a dual mechanism, by directly binding to GABA receptors (GABA Rs) and to the mitochondrial 18-kDa translocator protein, resulting in the potentiation of the GABAergic function. The β subunit subtype plays a key role in the EFX-GABA R interaction, however this does not explain the anxiolytic effects of this drug. Here, we combined behavioral and electrophysiological experiments to challenge the role of the GABA R α subunit in the EFX mode of action. After single administrations of anxiolytic doses (25-50 mg/kg, intraperitoneal), EFX did not induce any neurological nor locomotor impairments, unlike the benzodiazepine bromazepam (0.5-1 mg/kg, intraperitoneal). We established the EFX pharmacological profile on heteropentameric GABA Rs constructed with α1 to α6 subunit expressed in Xenopus oocyte. Unlike what is known for benzodiazepines, neither the γ nor δ subunits influenced EFX-mediated potentiation of GABA-evoked currents. EFX acted first as a partial agonist on α2β3γ2S, α3β3γ2S, α6β3γ2S and α6β3δ GABA Rs, but not on α1β3γ2S, α4β3γ2S, α4β3δ nor α5β3γ2S GABA Rs. Moreover, EFX exhibited much higher positive allosteric modulation towards α2β3γ2S, α3β3γ2S and α6β3γ2S than for α1β3γ2S, α4β3γ2S and α5β3γ2S GABA Rs. At 20 μM, corresponding to brain concentration at anxiolytic doses, EFX increased GABA potency to the highest extent for α3β3γ2S GABA Rs. We built a docking model of EFX on α3β3γ2S GABA Rs, which is consistent with a binding site located between α and β subunits in the extracellular domain. In conclusion, EFX preferentially potentiates α2β3γ2S and α3β3γ2S GABA Rs, which might support its advantageous anxiolytic/sedative balance.
ISSN:1096-1186
DOI:10.1016/j.phrs.2019.04.034