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

Caffeine has been shown to increase brain and plasma content of neurosteroid 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP) that allosterically modulates GABAA 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 GABAA agonist muscimol, or the benzodiazepine receptor agonist diazepam. On the contrary, caffeine produced higher anxiety in animals previously treated with the GABAA 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 GABAA 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 GABAA receptor activity may serve as a counter-regulatory mechanism against caffeine-induced anxiety.