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

Production of 5α-Reduced Neurosteroids Is Developmentally Regulated and Shapes GABAAMiniature IPSCs in Lamina II of the Spinal Cord

“…Our results indicate that activation of the PBR lead to the production of 5␣-reduced neurosteroids at a concentration sufficient to potentiate the function of synaptic GABA A receptors. These results are in good agreement with our previous in vitro study (Schlichter et al, 2000), realized on cultured hypothalamic neurons, which showed that the nonbenzodiazepine anxiolytic etifoxine increased GABA A receptor-mediated synaptic transmission in part by stimulation of the activity of PBR. The hypothesis of a neosynthesis of neurosteroid is further supported by the long delay (Ͼ1 hr) required to observe a modulation when DZP was perfused in the presence of the CBR antagonist FLU.…”

Investigation of the anticonvulsive effect of acute immobilization stress in anxious Balb/cByJ mice using GABAA-related mechanistic probes

“…Because it is accepted that the anxiolytic and anticonvulsive activities of progesterone are mainly mediated by its 5α-reduced metabolites, predominantly allopregnanolone, (Bitran et al 1995;Kokate et al 1999;Reddy et al 2005), prevention of the conversion of endogenously and exogenously administered progesterone to allopregnanolone in the presence of finasteride may explain the lack of effect of progesterone. The fact that etifoxine inhibited the effect of finasteride is consistent with previous studies showing that the direct activation by this compound of a site near or on the chloride channel coupled to the GABA A receptor was associated with an enhancement of GABA function (Verleye et al 1999;Schlichter et al 2000). However, recent studies have revealed that the effects of etifoxine on the GABA A receptor could also be mediated indirectly by an increase in neuroactive steroids levels in the brain (Verleye et al 2005).…”

Etifoxine improves peripheral nerve regeneration and functional recovery

“…However, TSPO ligands experimentally shown to exert beneficial actions on the peripheral nervous system have not found clinical utility, and possible side effects are a concern for their clinical use. Recent experimental studies demonstrated that the drug etifoxine (2-ethylamino-6-chloro-4-methyl-4-phenyl-4H-3, 1-benzoxazine hydrochloride; Stresam, Biocodex) exerts its anxiolytic effects by targeting GABA A receptors but also TSPO (14,15). Indeed, specific binding of the selective TSPO ligand PK11195 to membrane preparations of the rat brain is noncompetitively inhibited by etifoxine, which decreases both B max and K d (15).…”