R. W. Olsen and W. Sieghart, International Union of Pharmacology. LXX. Subtypes of gamma-616 aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, 617 and function. Update, Pharmacol Rev, vol.60, issue.3, pp.243-60, 2008.

M. Farrant and Z. Nusser, Variations on an inhibitory theme: phasic and tonic activation of 619 GABA(A) receptors, Nat Rev Neurosci, vol.6, issue.3, pp.215-244, 2005.

R. W. Olsen and W. Sieghart, GABA A receptors: subtypes provide diversity of function and 621 pharmacology, Neuropharmacology, vol.56, issue.1, pp.141-149, 2009.

E. Engin, R. S. Benham, and U. Rudolph, An Emerging Circuit Pharmacology of GABAA Receptors, p.623

, Trends Pharmacol Sci, vol.39, issue.8, pp.710-732, 2018.

T. Atkin, S. Comai, and G. Gobbi, Drugs for Insomnia beyond Benzodiazepines, p.625

, Clinical Applications, and Discovery, vol.70, issue.2, pp.197-245, 2018.

M. J. Brodie, F. Besag, A. B. Ettinger, M. Mula, G. Gobbi et al.,

E. Steinhoff, Antiepileptic Drugs, and Aggression: An Evidence-Based Review, Pharmacol, vol.628, issue.3, pp.563-602, 2016.

D. B. Pritchett, H. Sontheimer, B. D. Shivers, S. Ymer, H. Kettenmann et al.,

. Seeburg, Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology, Nature, vol.631, issue.6216, pp.582-587, 1989.

L. Steru, B. Thierry, R. Chermat, B. Millet, P. Simon et al., Comparing benzodiazepines 633 using the staircase test in mice, Psychopharmacology (Berl), vol.92, issue.1, pp.106-115, 1987.

M. Bourin, M. Hascoet, B. Mansouri, M. C. Colombel, and J. Bradwejn, Comparison of behavioral 635 effects after single and repeated administrations of four benzodiazepines in three mice behavioral 636 models, J Psychiatry Neurosci, vol.17, issue.2, pp.72-79, 1992.

U. Rudolph and F. Knoflach, Beyond classical benzodiazepines: novel therapeutic potential of 638 GABAA receptor subtypes, Nat Rev Drug Discov, vol.10, issue.9, pp.685-97, 2011.

U. Rudolph, F. Crestani, D. Benke, I. Brunig, J. A. Benson et al.,

H. Bluethmann and . Mohler, Benzodiazepine actions mediated by specific gamma-aminobutyric 641 acid(A) receptor subtypes, Nature, vol.401, issue.6755, pp.796-800, 1999.

R. M. Mckernan, T. W. Rosahl, D. S. Reynolds, C. Sur, K. A. Wafford et al.,

G. Myers, P. Cook, L. Ferris, L. Garrett, G. Bristow et al., , p.644

K. W. Moore, R. W. Carling, L. J. Street, J. L. Castro, C. I. Ragan et al., , p.645

, Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor 646 alpha1 subtype, Nat Neurosci, vol.3, issue.6, pp.587-92, 2000.

K. Löwe, F. Crestani, R. Keist, D. Benke, I. Brunig et al., , p.648

H. Bluethmann, U. Mohler, and . Rudolph, Molecular and neuronal substrate for the selective attenuation 649 of anxiety, Science, vol.290, issue.5489, pp.131-135, 2000.

R. Dias, W. F. Sheppard, R. L. Fradley, E. M. Garrett, J. L. Stanley et al.,

S. M. Lincoln, R. Cook, D. Conley, A. C. Hallett, S. A. Humphries et al.,

J. L. Street, P. J. Castro, T. W. Whiting, J. R. Rosahl, R. M. Atack et al.,

. Reynolds, Evidence for a significant role of alpha 3-containing GABAA receptors in mediating the 654 anxiolytic effects of benzodiazepines, J Neurosci, vol.25, issue.46, pp.10682-10690, 2005.

J. R. Atack, GABAA receptor alpha2/alpha3 subtype-selective modulators as potential 656 nonsedating anxiolytics, Curr Top Behav Neurosci, vol.2, pp.331-60, 2010.

M. M. Savic, S. Huang, R. Furtmuller, T. Clayton, S. Huck et al.,

D. R. Sieghart, J. M. Bokonjic, and . Cook, Are GABAA receptors containing alpha5 subunits contributing 659 to the sedative properties of benzodiazepine site agonists?, Neuropsychopharmacology, vol.33, issue.2, p.660, 2008.

L. M. Behlke, R. A. Foster, J. Liu, D. Benke, R. S. Benham et al.,

E. Zeilhofer, U. Engin, . Rudolph, and . Pharmacogenetic, Restriction-of-Function, Approach Reveals, vol.663

, Evidence for Anxiolytic-Like Actions Mediated by alpha5-Containing GABAA Receptors in Mice, p.664

, Neuropsychopharmacology, vol.41, issue.10, pp.2492-501, 2016.

J. R. Boissier, P. Simon, M. Zaczinska, and J. Fichelle, Experimental psychopharmacologic study 666 of a new psychotropic drug, 2-ethylamino-6-chloro-4-methyl-4-phenyl, p.667

, Therapie, vol.27, issue.2, pp.325-363, 1972.

N. Nguyen, E. Fakra, V. Pradel, E. Jouve, C. Alquier et al., , p.669

, Efficacy of etifoxine compared to lorazepam monotherapy in the treatment of patients with 670 adjustment disorders with anxiety: a double-blind controlled study in general practice, Hum 671 Psychopharmacol, vol.21, issue.3, pp.139-188, 2006.

D. J. Stein, Etifoxine versus alprazolam for the treatment of adjustment disorder with anxiety: a 673 randomized controlled trial, Adv Ther, vol.32, issue.1, pp.57-68, 2015.

M. Aouad, N. Petit-demouliere, Y. Goumon, and P. Poisbeau, Etifoxine stimulates 675 allopregnanolone synthesis in the spinal cord to produce analgesia in experimental 676 mononeuropathy, Eur J Pain, vol.18, issue.2, pp.258-68, 2014.

E. Simon-o'brien, D. Gauthier, V. Riban, and M. Verleye, Etifoxine improves sensorimotor deficits 678 and reduces glial activation, neuronal degeneration, and neuroinflammation in a rat model of 679 traumatic brain injury, J Neuroinflammation, vol.13, issue.1, p.203, 2016.

R. Schlichter, V. Rybalchenko, P. Poisbeau, M. Verleye, and J. Gillardin, , p.681

, GABAergic synaptic transmission by the non-benzodiazepine anxiolytic etifoxine, Neuropharmacology, vol.682, issue.9, pp.1523-1558, 2000.

A. Hamon, A. Morel, B. Hue, M. Verleye, and J. M. Gillardin, The modulatory effects of the 684 anxiolytic etifoxine on GABA(A) receptors are mediated by the beta subunit, Neuropharmacology, vol.685, issue.3, pp.293-303, 2003.

M. Verleye, Y. Akwa, P. Liere, N. Ladurelle, A. Pianos et al.,

. Gillardin, The anxiolytic etifoxine activates the peripheral benzodiazepine receptor and increases 688 the neurosteroid levels in rat brain, Pharmacol Biochem Behav, vol.82, issue.4, pp.712-732, 2005.

B. Costa, C. Cavallini, E. Da-pozzo, S. Taliani, F. Da et al., The Anxiolytic, p.690

, Etifoxine Binds to TSPO Ro5-4864 Binding Site with Long Residence Time Showing a High 691 Neurosteroidogenic Activity, ACS Chem Neurosci, vol.8, issue.7, pp.1448-1454, 2017.

P. Liere, A. Pianos, J. P. Oudinet, M. Schumacher, and Y. Akwa, Differential effects of the 18-kDa 693 translocator protein (TSPO) ligand etifoxine on steroidogenesis in rat brain, plasma and 694 steroidogenic glands: Pharmacodynamic studies, Psychoneuroendocrinology, vol.83, pp.122-134, 2017.

M. Verleye, R. Schlichter, and J. M. Gillardin, Interactions of etifoxine with the chloride channel 696 coupled to the GABA(A) receptor complex, Neuroreport, vol.10, issue.15, pp.3207-3217, 1999.

M. Verleye, I. Heulard, and J. M. Gillardin, Investigation of the anticonvulsive effect of acute 698 immobilization stress in anxious Balb/cByJ mice using GABA A-related mechanistic probes, p.699

, Psychopharmacology (Berl), vol.197, issue.4, pp.523-557, 2008.

M. Verleye, I. Heulard, P. Nuss, and J. M. Gillardin, Effects of stress and etifoxine on pentobarbital-701 induced loss of righting reflex in Balb/cByJ and C57BL/6J mice, Neurosci Lett, vol.353, issue.2, p.127, 2003.

M. Sansone, Benzodiazepines and amphetamine on avoidance behaviour in mice, Arch Int, vol.704

, Pharmacodyn Ther, vol.218, issue.1, pp.125-157, 1975.

R. B. Rastogi, Y. D. Lapierre, and R. L. Singhal, Effect of a new benzodiazepine bromazepam on 706 locomotor performance and brain monoamine metabolism, J Neural Transm, vol.42, issue.4, pp.251-61, 1978.

M. Verleye, S. Dumas, I. Heulard, N. Krafft, and J. M. Gillardin, Differential effects of etifoxine on 708 anxiety-like behaviour and convulsions in BALB/cByJ and C57BL/6J mice: any relation to 709 overexpression of central GABAA receptor beta2 subunits?, Eur Neuropsychopharmacol, vol.21, issue.6, pp.457-70, 2011.

B. Olivier, T. Zethof, T. Pattij, M. Van-boogaert, R. Van-oorschot et al.,

J. Bouwknecht, J. Veening, L. Van-der-gugten, and . Groenink, Stress-induced hyperthermia and anxiety: 713 pharmacological validation, Eur J Pharmacol, vol.463, issue.1-3, pp.117-149, 2003.

T. J. Zethof, J. A. Van-der-heyden, J. T. Tolboom, and B. Olivier, Stress-induced hyperthermia in 715 mice: a methodological study, Physiol Behav, vol.55, issue.1, pp.109-124, 1994.

J. A. Van-der-heyden, T. J. Zethof, and B. Olivier, Stress-induced hyperthermia in singly housed 717 mice, Physiol Behav, vol.62, issue.3, pp.463-70, 1997.

S. F. De-boer and J. M. Koolhaas, Defensive burying in rodents: ethology, neurobiology and 719 psychopharmacology, Eur J Pharmacol, vol.463, issue.1-3, pp.145-61, 2003.

A. Walker, J. Taylor, D. Rowe, and D. Summers, A method for generating sticky-end PCR products 721 which facilitates unidirectional cloning and the one-step assembly of complex DNA constructs, Plasmid, vol.722, issue.3, pp.155-62, 2008.

S. P. Venkatachalan, J. D. Bushman, J. L. Mercado, F. Sancar, K. R. Christopherson et al., , p.724

, Optimized expression vector for ion channel studies in Xenopus oocytes and mammalian cells using 725 alfalfa mosaic virus, Pflugers Arch, vol.454, issue.1, pp.155-63, 2007.

A. Draguhn, T. A. Verdorn, M. Ewert, P. H. Seeburg, and B. Sakmann, Functional and molecular 727 distinction between recombinant rat GABAA receptor subtypes by Zn 2+, Neuron, vol.5, issue.6, pp.781-789, 1990.

C. Notredame, D. G. Higgins, and J. Heringa, T-Coffee: A novel method for fast and accurate 729 multiple sequence alignment, J Mol Biol, vol.302, issue.1, pp.205-222, 2000.

A. Sali and T. L. Blundell, Comparative protein modelling by satisfaction of spatial restraints, J 731 Mol Biol, vol.234, issue.3, pp.779-815, 1993.

G. G. Krivov, M. V. Shapovalov, and R. L. Dunbrack, Improved prediction of protein side-chain 733 conformations with SCWRL4, Proteins, vol.77, issue.4, pp.778-95, 2009.

B. R. Brooks, C. L. Brooks, A. D. Mackerell, L. Nilsson, R. J. Petrella et al., , p.735

G. Archontis, C. Bartels, S. Boresch, A. Caflisch, L. Caves et al.,

J. Fischer, M. Gao, W. Hodoscek, K. Im, T. Kuczera et al., , p.737

R. W. Pastor, C. B. Post, J. Z. Pu, M. Schaefer, B. Tidor et al.,

D. M. Yang, M. York, and . Karplus, CHARMM: the biomolecular simulation program, J Comput Chem, vol.739, issue.10, pp.1545-614, 2009.

J. Henin, R. Salari, S. Murlidaran, and G. Brannigan, A predicted binding site for cholesterol on the 741 GABAA receptor, Biophys J, vol.106, issue.9, pp.1938-1987, 2014.

O. Trott and A. J. Olson, AutoDock Vina: improving the speed and accuracy of docking with a new 743 scoring function, efficient optimization, and multithreading, J Comput Chem, vol.31, issue.2, pp.455-61, 2010.

R. R. Ugale, A. N. Sharma, D. M. Kokare, K. Hirani, N. K. Subhedar et al., Neurosteroid 745 allopregnanolone mediates anxiolytic effect of etifoxine in rats, Brain Res, vol.1184, pp.193-201, 2007.

A. Barberis, E. M. Petrini, and J. W. Mozrzymas, Impact of synaptic neurotransmitter concentration 747 time course on the kinetics and pharmacological modulation of inhibitory synaptic currents, Front 748 Cell Neurosci, vol.5, p.6, 2011.

H. You, J. L. Kozuska, I. M. Paulsen, and S. M. Dunn, Benzodiazepine modulation of the rat 750 GABAA receptor alpha4beta3gamma2L subtype expressed in Xenopus oocytes, Neuropharmacology, vol.751, issue.6, pp.527-560, 2010.

Z. Nusser, W. Sieghart, and P. Somogyi, Segregation of different GABAA receptors to synaptic and 753 extrasynaptic membranes of cerebellar granule cells, J Neurosci, vol.18, issue.5, pp.1693-703, 1998.

M. A. Lomize, I. D. Pogozheva, H. Joo, H. I. Mosberg, and A. L. Lomize, OPM database and PPM 755 web server: resources for positioning of proteins in membranes, Nucleic Acids Res, vol.40, pp.370-376, 2012.

C. Bouillot, F. Bonnefoi, F. Liger, and L. Zimmer, A microPET comparison of the effects of 758 etifoxine and diazepam on [(11)C]flumazenil uptake in rat brains, Neurosci Lett, vol.612, pp.74-83, 2016.

P. L. Toutain and A. Bousquet-melou, Free drug fraction vs free drug concentration: a matter of 760 frequent confusion, J Vet Pharmacol Ther, vol.25, issue.6, pp.460-463, 2002.

T. S. Maurer, D. B. Debartolo, D. A. Tess, and D. O. Scott, Relationship between exposure and 762 nonspecific binding of thirty-three central nervous system drugs in mice, Drug Metab Dispos, vol.33, issue.1, pp.175-81, 2005.

S. G. Summerfield, K. Read, D. J. Begley, T. Obradovic, I. J. Hidalgo et al., , p.765

R. A. Porter and P. Jeffrey, Central nervous system drug disposition: the relationship between in situ 766 brain permeability and brain free fraction, J Pharmacol Exp Ther, vol.322, issue.1, pp.205-218, 2007.

A. Lippa, P. Czobor, J. Stark, B. Beer, E. Kostakis et al.,

T. T. Russek, D. H. Gibbs, P. Farb, and . Skolnick, Selective anxiolysis produced by ocinaplon, a 769 GABA(A) receptor modulator, Proc Natl Acad Sci U S A, vol.102, issue.20, pp.7380-7385, 2005.

M. Verleye and J. M. Gillardin, Effects of etifoxine on stress-induced hyperthermia, freezing 771 behavior and colonic motor activation in rats, Physiol Behav, vol.82, issue.5, pp.891-898, 2004.

R. D. Porsolt, A. Lenegre, I. Avril, and G. Doumont, Antagonism by exifone, a new cognitive 773 enhancing agent, of the amnesias induced by four benzodiazepines in mice, Psychopharmacology, vol.774, issue.3, pp.291-298, 1988.

J. Micallef, C. Soubrouillard, F. Guet, M. E. Le-guern, C. Alquier et al., A 776 double blind parallel group placebo controlled comparison of sedative and mnesic effects of 777 etifoxine and lorazepam in healthy subjects, Fundam Clin Pharmacol, vol.15, issue.3, p.209, 2001.

D. Deplanque, F. Machuron, N. Waucquier, E. Jozefowicz, S. Duhem et al.,

R. Duhamel and . Bordet, Etifoxine impairs neither alertness nor cognitive functions of the elderly: A 781 randomized, double-blind, placebo-controlled crossover study, Eur Neuropsychopharmacol, vol.28, issue.8, pp.925-932, 2018.

L. Wolf, A. Bauer, D. Melchner, H. Hallof-buestrich, P. Stoertebecker et al.,

V. M. Sarubin, C. H. Milenkovic, R. Wetzel, C. Rupprecht, and . Nothdurfter, Enhancing neurosteroid 785 synthesis--relationship to the pharmacology of translocator protein (18 kDa) (TSPO) ligands and 786 benzodiazepines, Pharmacopsychiatry, vol.48, issue.2, pp.72-79, 2015.

D. Belelli, A. Casula, A. Ling, and J. J. Lambert, The influence of subunit composition on the 788 interaction of neurosteroids with GABA(A) receptors, Neuropharmacology, vol.43, issue.4, pp.651-61, 2002.

M. C. Gravielle, Activation-induced regulation of GABAA receptors: Is there a link with the 790 molecular basis of benzodiazepine tolerance?, Pharmacol Res, vol.109, pp.92-100, 2016.

J. R. Atack, K. A. Wafford, S. J. Tye, S. M. Cook, B. Sohal et al.,

F. Bristow, I. Bromidge, J. Ragan, L. Kerby, R. Street et al.,

R. M. Dawson and . Mckernan, 1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-794 ylmethoxy)-3-(2-fluorophenyl )-1,2,4-triazolo[4,3-b]pyridazine], an agonist selective for alpha2-795 and alpha3-containing GABAA receptors, is a nonsedating anxiolytic in rodents and primates, J 796 Pharmacol Exp Ther, vol.316, issue.7, pp.410-432, 2006.

E. P. Christian, D. H. Snyder, W. Song, D. A. Gurley, J. Smolka et al.,

X. F. Gharahdaghi, M. Liu, M. Chopra, M. J. Ribadeneira, A. Chapdelaine et al.,

M. C. Maciag, J. J. Quirk, and . Doherty, EEG-beta/gamma spectral power elevation in rat: a translatable 800 biomarker elicited by GABA(Aalpha2/3)-positive allosteric modulators at nonsedating anxiolytic 801 doses, J Neurophysiol, vol.113, issue.1, pp.116-147, 2015.

B. D. Fischer, J. R. Atack, D. M. Platt, D. S. Reynolds, G. R. Dawson et al., Contribution 803 of GABA(A) receptors containing alpha3 subunits to the therapeutic-related and side effects of 804 benzodiazepine-type drugs in monkeys, Psychopharmacology (Berl), vol.215, issue.2, pp.311-320, 2011.

A. G. De-lucas, P. K. Ahring, J. S. Larsen, I. Rivera-arconada, J. A. Lopez-garcia et al., , p.806

G. Munro, GABAA alpha5 subunit-containing receptors do not contribute to reversal of 807 inflammatory-induced spinal sensitization as indicated by the unique selectivity profile of the 808 GABAA receptor allosteric modulator NS16085, Biochem Pharmacol, vol.93, issue.3, pp.370-379, 2015.

J. Simon, H. Wakimoto, N. Fujita, M. Lalande, and E. A. Barnard, Analysis of the set of GABA(A) 810 receptor genes in the human genome, J Biol Chem, vol.279, issue.40, pp.41422-41457, 2004.

S. Zhu, C. M. Noviello, J. Teng, R. M. Walsh, J. J. Kim et al., Structure of a human 812 synaptic GABAA receptor, Nature, vol.559, issue.7712, pp.67-72, 2018.