Involvement of the GABAA receptor α subunit in the mode of action of etifoxine

Abstract

Etifoxine (EFX) is a non-benzodiazepine psychoactive drug which exhibits anxiolytic effects through a dual mechanism, by directly binding to GABA A receptors (GABA A 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 A 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 A 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 A 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 A Rs, but not on α1β3γ2S, α4β3γ2S, α4β3δ nor α5β3γ2S GABA A Rs. Moreover, EFX exhibited much higher positive allosteric modulation towards α2β3γ2S, α3β3γ2S and α6β3γ2S than for α1β3γ2S, α4β3γ2S and α5β3γ2S GABA A Rs. At 20 μM, corresponding to brain concentration at anxiolytic doses, EFX increased GABA potency to the highest extent for α3β3γ2S GABA A Rs. We built a docking model of EFX on α3β3γ2S GABA A 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 A Rs, which might support its advantageous anxiolytic/sedative balance.