Neuroactive Steroid 3α-Hydroxy-5α-Pregnan-20-One Modulates Electrophysiological and Behavioral Actions of Ethanol

Abstract

Neuroactive steroids are synthesized de novo in brain, yet their physiological significance remains elusive. We provide biochemical, electrophysiological, and behavioral evidence that several specific actions of alcohol (ethanol) are mediated by the neurosteroid 3␣-hydroxy-5␣-pregnan-20-one (3␣,5␣-THP; allopregnanolone). Systemic alcohol administration elevates 3␣,5␣-THP levels in the cerebral cortex to pharmacologically relevant concentrations. The elevation of 3␣,5␣-THP is doseand time-dependent. Furthermore, there is a significant correlation between 3␣,5␣-THP levels in cerebral cortex and the hypnotic effect of ethanol. Blockade of de novo biosynthesis of 5␣-reduced steroids using the 5␣-reductase inhibitor finasteride prevents several effects of ethanol. Pretreatment with finasteride causes no changes in baseline bicuculline-induced seizure threshold but reverses the anticonvulsant effect of ethanol. Finasteride pretreatment also reverses ethanol inhibition of spontaneous neural activity in medial septal/diagonal band of Broca neurons while having no direct effect on spontaneous firing rates. Thus, elevation of 3␣,5␣-THP levels by acute ethanol administration represents a novel mechanism of ethanol action as well as an important modulatory role for neurosteroids in the CNS.

GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated by Finasteride

“…Studies in chronic drinkers have shown 40-50% lower plasma concentrations of ALLO and THDOC in the first week of abstinence, with normalization during the subsequent 3 weeks (Romeo et al, 1996(Romeo et al, , 2000. These studies suggest a direct link between increased neuroactive steroid levels and acute alcohol intoxication in humans, with chronic intoxication producing the opposite effect, findings that parallel those described in the animal literature (Barbaccia et al, 1999;VanDoren et al, 2000;Khisti et al, 2003;Finn et al, 2004).…”

“…In rats, the time course of the alcohol-induced increase in brain ALLO concentration paralleled the appearance of specific behavioral and electrophysiological effects of alcohol (Finn et al, 2004;VanDoren et al, 2000), which were reversed by finasteride (VanDoren et al, 2000;Khisti et al, 2003). Finasteride also reduced the numbing effects of alcohol, as measured by the SS Anesthetic Subscale.…”

“…As alcohol elevates plasma and brain concentrations of GABAergic neuroactive steroids, including 3a-5a-THP (allopregnanolone or ALLO), and 3a-5a-THDOC (allotetrahydrodeoxycorticosterone), it has been hypothesized that these compounds may contribute to specific behavioral actions of ethanol by modulating GABA A receptor function (Morrow et al, 1999;Barbaccia et al, 1999;VanDoren et al, 2000). Two recent reports in humans suggest that acute alcohol exposure stimulates neuroactive steroid production Ortega, 2003, 2004).…”

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

“…VanDoren et al (2000) were able to reduce the anticonvulsant action of ethanol and completely block the effect of moderate concentrations of ethanol on medial septal neurons by minimizing the production of neurosteroids with the 5a-reductase inhibitor finasteride. Likewise, Tokunaga et al (2003) demonstrated a reduction of ethanol action on neural activity in the hippocampus by inhibiting neuroactive steroid production.…”

Olanzapine and Clozapine Increase the GABAergic Neuroactive Steroid Allopregnanolone in Rodents

“…Allopregnanolone levels were measured in the cerebral cortex as described previously (Janis et al, 1998;VanDoren et al, 2000) with a modification of the methods of Purdy et al (1990). Allopregnanolone was extracted from individual cerebral cortical hemispheres prior to RIA determination.…”