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

We have investigated the effects of 2-ethylamino-6-chloro-4-methyl-4-phenyl -4H-3,1-benzoxazine hydrochloride (etifoxine) on GABA(A) receptor function. Etifoxine displaced [S-35]TBPS (t-butylbicyclophosphorothionate) from GABA (A) receptors of rat cortical membranes with an IC50 of 6.7+/-0.8 mu M and [H-3]PK11195 from peripheral (mitochondrial)-type benzodiazepine receptors (PBRs) of rat heart homogenates with an IC50 of 27.3+/-1.0 mu M Etifoxine d isplayed anxiolytic properties in an anticonflict test in rats, and potenti ated GABA(A) receptor-mediated membrane currents elicited by submaximal (5- 10 mu M) but not saturating (0.5 mM) concentrations of GABA in cultured rat hypothalamic and spinal cord dorsal horn neurones. In hypothalamic culture s, etifoxine induced a dose-dependent inward current for concentrations >1 mu M which reflected the post-synaptic potentiation of a small (similar to 20 pA) tonic and bicuculline-sensitive GABA(A) receptor-gated Cl- current. Etifoxine also increased the frequency of spontaneous and miniature GABAerg ic inhibitory post-synaptic currents without changing their amplitude and k inetic characteristics. Both effects of etifoxine were insensitive to fluma zenil (10 mu M), an antagonist of central-type benzodiazepine sites present at GABA(A) receptors, but were partly inhibited by PK11195 (10 mu M) an an tagonist of PBRs which control the synthesis of neurosteroids. Our results indicate that etifoxine potentiates GABA(A) receptor-function by a direct a llosteric effect and by an indirect mechanism involving the activation of P BRs. (C) 2000 Elsevier Science Ltd. All rights reserved.