J. Neurochem. (2010) 115, 142–152.
Abstract
Acute ethanol administration increases potent GABAergic neuroactive steroids, specifically (3α,5α)‐3‐hydroxypregnan‐20‐one (3α,5α‐THP) and (3α,5α)‐3,21‐dihydroxypregnan‐20‐one. In addition, neuroactive steroids contribute to ethanol actions. Chronic ethanol exposure results in tolerance to many effects of ethanol, including ethanol‐induced increases in neuroactive steroid levels. To determine the mechanisms of tolerance to ethanol‐induced increases in neuroactive steroids, we investigated critical signaling molecules that are required for acute ethanol effects. Male Sprague‐Dawley rats were administered ethanol via liquid diet for 2 weeks and steroid levels, adrenocorticotrophic hormone (ACTH) and adrenal steroidogenic acute regulatory (StAR) protein expression were measured. Chronic ethanol exposure elicits tolerance to ethanol‐induced elevation of serum ACTH and the steroids pregnenolone and progesterone. Surprisingly, chronic ethanol exposure does not result in tolerance to ethanol‐induced increases in adrenal StAR protein. However, ethanol‐induced StAR phosphorylation is decreased when compared to acute ethanol administration. A separate group of rats exposed to chronic ethanol diet were subsequently challenged with ethanol (2 g/kg) and exhibited a blunted elevation of serum ACTH and progesterone as well as cerebral cortical and hippocampal 3α,5α‐THP. Administration of ACTH with the ethanol challenge restored the elevation of serum ACTH and progesterone as well as cerebral cortical 3α,5α‐THP levels to those observed in ethanol‐naïve rats. Thus, chronic ethanol exposure disrupts ACTH release, which results in tolerance to ethanol‐induced increases in neuroactive steroid levels. Loss of the ethanol‐induced increases in neuroactive steroids may contribute to behavioral tolerance to ethanol and influence the progression towards alcoholism.