Neurosteroid allopregnanolone mediates anxiolytic effect of etifoxine in rats

Abstract

Etifoxine (6-chloro-2-ethylamino-4-methyl-4-phenyl-4H-3,1-benzoxazine hydrochloride), a nonbenzodiazepine anxiolytic drug, potentiates GABA(A) receptor function perhaps through stimulation of neurosteroid biosynthesis. However, the exact mechanism of etifoxine action is not fully understood. In this study, we have assessed the possible role of GABAergic neurosteroid like allopregnanolone (ALLO) in the anxiolytic-like effect of etifoxine in rats using elevated plus maze test. Selective GABA(A) receptor agonist, muscimol, ALLO or neurosteroidogenic agents like progesterone, metyrapone or mitochondrial diazepam binding inhibitor receptor (MDR) agonist, FGIN 1-27 significantly heightened the etifoxine-induced anxiolysis. On the other hand, GABA(A) receptor antagonist, bicuculline or neurosteroid biosynthesis inhibitors like finasteride, indomethacin, trilostane or PBR antagonist, PK11195 significantly blocked the effect of etifoxine. Bilateral adrenalectomy did not influence anti-anxiety effect of etifoxine thereby ruling out contribution of adrenal steroids. Thus, our results provide behavioral evidence for the role of neurosteroids like ALLO in the anti-anxiety effect of etifoxine.