Chronic ethanol exposure produces tolerance to elevations in neuroactive steroids: mechanisms and reversal by exogenous ACTH.
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.
Boyd
Kevin N
KN
Curriculum in Toxicology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Kumar
Sandeep
S
O'Buckley
Todd K
TK
Morrow
A Leslie
AL
D000324:Adrenocorticotropic Hormone / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002492:Central Nervous System Depressants / Q000633:toxicity*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004032:Diet; D004361:Drug Tolerance; D000431:Ethanol / Q000633:toxicity*; D047468:Immunoprecipitation; D008297:Male; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000096:biosynthesis*; D010750:Phosphoproteins / Q000502:physiology; D010766:Phosphorylation; D011284:Pregnenolone / Q000096:biosynthesis*; D011374:Progesterone / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
D002492:Central Nervous System Depressants; D018377:Neurotransmitter Agents; D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D000431:Ethanol; D011374:Progesterone; D005680:gamma-Aminobutyric Acid; D011284:Pregnenolone; D000324:Adrenocorticotropic Hormone; D017868:Cyclic AMP-Dependent Protein Kinases