Modulation of GABAergic synaptic transmission by the non-benzodiazepine anxiolytic etifoxine

Abstract

We have investigated the effects of 2-ethylamino-6-chloro-4-methyl-4-phenyl-4 H-3,1-benzoxazine hydrochloride (etifoxine) on GABA A receptor function. Etifoxine displaced [ 35S]TBPS ( t-butylbicyclophosphorothionate) from GABA A receptors of rat cortical membranes with an IC 50 of 6.7±0.8 μM and [ 3H]PK11195 from peripheral (mitochondrial)-type benzodiazepine receptors (PBRs) of rat heart homogenates with an IC 50 of 27.3±1.0 μM. Etifoxine displayed anxiolytic properties in an anticonflict test in rats, and potentiated GABA A receptor-mediated membrane currents elicited by submaximal (5–10 μM) but not saturating (0.5 mM) concentrations of GABA in cultured rat hypothalamic and spinal cord dorsal horn neurones. In hypothalamic cultures, etifoxine induced a dose-dependent inward current for concentrations >1 μM which reflected the post-synaptic potentiation of a small (∼20 pA) tonic and bicuculline-sensitive GABA A receptor-gated Cl − current. Etifoxine also increased the frequency of spontaneous and miniature GABAergic inhibitory post-synaptic currents without changing their amplitude and kinetic characteristics. Both effects of etifoxine were insensitive to flumazenil (10 μM), an antagonist of central-type benzodiazepine sites present at GABA A receptors, but were partly inhibited by PK11195 (10 μM) an antagonist of PBRs which control the synthesis of neurosteroids. Our results indicate that etifoxine potentiates GABA A receptor-function by a direct allosteric effect and by an indirect mechanism involving the activation of PBRs.