title: The anxiolytic etifoxine activates the peripheral benzodiazepine receptor and increases the neurosteroid levels in rat brain.
abstract: The peripheral benzodiazepine receptors (PBR) might be involved in certain pathophysiological events, such as anxiety, by stimulating the production of neuroactive steroids in the brain. A recent electrophysiological study has revealed an interaction between PK11195, a PBR ligand and the anxiolytic compound etifoxine at micromolar concentrations. The present work was aimed at further characterizing the etifoxine-PBR interaction. In membrane preparations from intact male rat forebrain, etifoxine uncompetitively inhibited the binding of [(3)H]PK11195 with an IC(50) = 18.3 +/- 1.2 microM, a value consistent with etifoxine plasma and brain concentrations measured after an anxiolytic-like dose (50 mg/kg). In vivo, that etifoxine dose was associated with increased concentrations of pregnenolone, progesterone, 5alpha-dihydroprogesterone and allopregnanolone in plasma and brain of sham-operated animals. In adrenalectomized and castrated rats, etifoxine enhanced the brain levels of these steroids, suggesting a stimulation of their local synthesis and/or a decrease of their disappearance rate, independently of peripheral sources. Finasteride, an inhibitor of 5alpha-reductase that converts progesterone into its 5alpha-reduced metabolites like allopregnanolone, attenuated the anti-conflict effect of etifoxine even though brain allopregnanolone contents were drastically reduced. These results indicate that following activation of the PBR in the brain, an increased cerebral production of allopregnanolone, a potent positive modulator of the GABA(A) receptor function, may partially contribute to the anxiolytic-like effects of etifoxine.
authors.affiliation: Département de Pharmacologie, Biocodex, Zac de Mercières, Chemin d'Armancourt, Compiègne, France. m.verleye@biocodex.fr
authors.forename: Marc
authors.initials: M
authors.lastname: Verleye
authors.forename: Yvette
authors.initials: Y
authors.lastname: Akwa
authors.forename: Philippe
authors.initials: P
authors.lastname: Liere
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ladurelle
authors.forename: Antoine
authors.initials: A
authors.lastname: Pianos
authors.forename: Bernard
authors.initials: B
authors.lastname: Eychenne
authors.forename: Michael
authors.initials: M
authors.lastname: Schumacher
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Gillardin
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D007546:Isoquinolines / Q000378:metabolism; D008297:Male; D010078:Oxazines / Q000494:pharmacology*; D011280:Pregnanolone / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects*; D013256:Steroids / Q000378:metabolism*
chemical_list: D014151:Anti-Anxiety Agents; D007546:Isoquinolines; D010078:Oxazines; D011963:Receptors, GABA-A; D013256:Steroids; D011280:Pregnanolone; C002125:etifoxine; C037850:PK 11195