Neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one modulates electrophysiological and behavioral actions of ethanol

Neuroactive steroids are synthesized de novo in brain, yet their physiologi cal significance remains elusive. We provide biochemical, electrophysiologi cal, and behavioral evidence that several specific actions of alcohol (etha nol) are mediated by the neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-on e (3 alpha,5 alpha-THP; allopregnanolone). Systemic alcohol administration elevates 3 alpha,5 alpha-THP levels in the cerebral cortex to pharmacologic ally relevant concentrations. The elevation of 3 alpha,5 alpha-THP is dose- and time-dependent. Furthermore, there is a significant correlation betwee n 3 alpha,5 alpha-THP levels in cerebral cortex and the hypnotic effect of ethanol. Blockade of de novo biosynthesis of 5 alpha-reduced steroids using the 5 alpha-reductase inhibitor finasteride prevents several effects of et hanol. Pretreatment with finasteride causes no changes in baseline bicucull ine-induced seizure threshold but reverses the anticonvulsant effect of eth anol. Finasteride pretreatment also reverses ethanol inhibition of spontane ous neural activity in medial septal/diagonal band of Broca neurons while h aving no direct effect on spontaneous firing rates. Thus, elevation of 3 al pha,5 alpha-THP levels by acute ethanol administration represents a novel m echanism of ethanol action as well as an important modulatory role for neur osteroids in the CNS.