The anxiolytic etifoxine activates the peripheral benzodiazepine receptor and increases the neurosteroid levels in rat brain

Pharmacol Biochem Behav. 2005 Dec;82(4):712-20. doi: 10.1016/j.pbb.2005.11.013. Epub 2006 Jan 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Brain / drug effects*
  • Brain / metabolism
  • Isoquinolines / metabolism
  • Male
  • Oxazines / pharmacology*
  • Pregnanolone / metabolism
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Receptors, GABA-A / drug effects*
  • Steroids / metabolism*


  • Anti-Anxiety Agents
  • Isoquinolines
  • Oxazines
  • Receptors, GABA-A
  • Steroids
  • Pregnanolone
  • etifoxine
  • PK 11195