Differential effects of the 18-kDa translocator protein (TSPO) ligand etifoxine on steroidogenesis in rat brain, plasma and steroidogenic glands: Pharmacodynamic studies

Abstract Etifoxine is indicated in humans for treating anxiety. In rodents, besides its anxiolytic-like properties, it has recently shown neuroprotective and neuroregenerative activities. It acts by enhancing GABA A receptor function and by stimulating acute steroid biosynthesis via the activation of the 18-kDa translocator protein. However, the regulatory action of etifoxine on steroid production is not well characterized. In this work, we performed dose-response, acute and chronic time-course experiments on the effects of intraperitoneal injections of etifoxine on steroid levels in adult male rat brain and plasma analyzed by gas chromatography-mass spectrometry. Concentrations of pregnenolone, progesterone and its 5α-reduced metabolites were significantly increased in both tissues in response to 25 and 50 mg/kg of etifoxine, as compared with vehicle controls, and reached maximal values at 0.5–1 h post-injection. Daily injections of etifoxine (50 mg/kg, 15 days) kept them increased at day 15. Comparisons between steroidogenic tissues revealed that 1 h after 50 mg/kg of etifoxine treatment, levels of pregnenolone, progesterone and corticosterone were highest in adrenal glands and markedly increased together with their reduced metabolites. They were also increased by etifoxine in brain and plasma, but not in testis except for corticosterone and its metabolites. In contrast, testosterone level was significantly decreased in testis while with its 5α-reduced metabolites, it was unchanged in brain. Results demonstrate that the modulation of steroid concentrations by etifoxine is dependent on the type of steroid and on the steroidogenic organ. They further suggest that adrenal steroids upregulated by etifoxine make an important contribution to the steroids present in brain. This work provides a precise and complete view of steroids regulated by etifoxine that could be useful in therapeutic research.