Reversal of caffeine-induced anxiety by neurosteroid 3-alpha-hydroxy-5-alpha-pregnane-20-one in rats

Abstract

Caffeine has been shown to increase brain and plasma content of neurosteroid 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP) that allosterically modulates GABA A receptors. The present study evaluated the role of neurosteroid 3α,5α-THP in the caffeine-induced anxiogenic-like effect using the elevated plus-maze (EPM) test in rats. Acute administration of caffeine (50 or 100 mg/kg, i.p.) produced anxiogenic-like activity that was reversed by pretreatment with the neurosteroid 3α,5α-THP or progesterone, the GABA A agonist muscimol, or the benzodiazepine receptor agonist diazepam. On the contrary, caffeine produced higher anxiety in animals previously treated with the GABA A receptor antagonist, bicuculline or either of the various neurosteroid biosynthesis enzyme inhibitors viz. trilostane, finasteride or indomethacin. Furthermore, pretreatment with DHEAS, a neurosteroid that negatively modulates GABA A receptors also enhanced the caffeine-induced anxiety. Moreover, adrenalectomy potentiated the anxiogenic-like response of caffeine indicating the contributory role of peripheral steroidogenesis. Thus, it is speculated that neurosteroid 3α,5α-THP through positive modulation of GABA A receptor activity may serve as a counter-regulatory mechanism against caffeine-induced anxiety.