Neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one modulates ethanol-induced loss of righting reflex in rats

Systemic ethanol administration elevates plasma and brain levels of GABAergic neuroactive steroids, including 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) that contribute to specific behavioral actions of ethanol. The present study determined the effect of adrenalectomy and 5alpha-reductase type-1/type-2 enzyme inhibition, known to reduce neuroactive steroids, on ethanol-induced increases in cerebral cortical levels of 3alpha,5alpha-THP and hypnotic effects in male rats. Systemic ethanol administration to male rats increases plasma levels of progesterone and corticosterone similar to acute stress, indicating release of these steroids from adrenal glands. Adrenalectomy markedly reduced the elevation of cerebral cortical 3alpha,5alpha-THP and plasma progesterone levels and reduced the duration of ethanol-induced loss of righting reflex. Prior systemic administration of 5alpha-dihydroprogesterone (10 or 15 mg/kg, i.p.), an immediate precursor of 3alpha,5alpha-THP, to adrenalectomized rats not only restored the ethanol-induced increases in cerebral cortical 3alpha,5alpha-THP levels but also reversed the effect of adrenalectomy on ethanol-induced loss of righting reflex. Prior administration of the 5alpha-reductase inhibitor finasteride (2 x 25, 2 x 75 or 2 x 150 mg/kg, s.c.) and the 5alpha-reductase type-1 inhibitor SKF-105,111 (50 mg/kg, i.p.) did not reduce ethanol-induced increases in the cerebral cortical levels of 3alpha,5alpha-THP at hypnotic doses of ethanol. Furthermore, these drugs did not alter the duration of loss of righting reflex. However, significant correlations between cerebral cortical 3alpha,5alpha-THP levels and the duration of loss of righting reflex were obtained regardless of finasteride administration. These results demonstrate the contributory role of neuroactive steroids in the ethanol-induced loss of righting reflex and the source of ethanol-induced elevation of GABAergic neuroactive steroids. Ethanol-induced increases in neurosteroids could be pertinent to the etiology of sleep-related disorders associated with alcoholism.