Differential Effects of Ethanol on Serum GABAergic 3α,5α/3α,5β Neuroactive Steroids in Mice, Rats, Cynomolgus Monkeys, and Humans

Authors

  • Patrizia Porcu,

    1. From the Department of Psychiatry and Bowles Center for Alcohol Studies (PP, TKO, SEA, SCS, ALM), University of North Carolina School of Medicine, Chapel Hill, North Carolina; Department of Behavioral Neurosciences (KAG), Oregon Health and Science University, and the Oregon National Primate Research Center, Portland, Oregon; Department of Psychiatry (HdW), The University of Chicago, Chicago, Illinois; and Department of Pharmacology (ALM), University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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  • Todd K. O’Buckley,

    1. From the Department of Psychiatry and Bowles Center for Alcohol Studies (PP, TKO, SEA, SCS, ALM), University of North Carolina School of Medicine, Chapel Hill, North Carolina; Department of Behavioral Neurosciences (KAG), Oregon Health and Science University, and the Oregon National Primate Research Center, Portland, Oregon; Department of Psychiatry (HdW), The University of Chicago, Chicago, Illinois; and Department of Pharmacology (ALM), University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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  • Sarah E. Alward,

    1. From the Department of Psychiatry and Bowles Center for Alcohol Studies (PP, TKO, SEA, SCS, ALM), University of North Carolina School of Medicine, Chapel Hill, North Carolina; Department of Behavioral Neurosciences (KAG), Oregon Health and Science University, and the Oregon National Primate Research Center, Portland, Oregon; Department of Psychiatry (HdW), The University of Chicago, Chicago, Illinois; and Department of Pharmacology (ALM), University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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  • Soomin C. Song,

    1. From the Department of Psychiatry and Bowles Center for Alcohol Studies (PP, TKO, SEA, SCS, ALM), University of North Carolina School of Medicine, Chapel Hill, North Carolina; Department of Behavioral Neurosciences (KAG), Oregon Health and Science University, and the Oregon National Primate Research Center, Portland, Oregon; Department of Psychiatry (HdW), The University of Chicago, Chicago, Illinois; and Department of Pharmacology (ALM), University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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  • Kathleen A. Grant,

    1. From the Department of Psychiatry and Bowles Center for Alcohol Studies (PP, TKO, SEA, SCS, ALM), University of North Carolina School of Medicine, Chapel Hill, North Carolina; Department of Behavioral Neurosciences (KAG), Oregon Health and Science University, and the Oregon National Primate Research Center, Portland, Oregon; Department of Psychiatry (HdW), The University of Chicago, Chicago, Illinois; and Department of Pharmacology (ALM), University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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  • Harriet De Wit,

    1. From the Department of Psychiatry and Bowles Center for Alcohol Studies (PP, TKO, SEA, SCS, ALM), University of North Carolina School of Medicine, Chapel Hill, North Carolina; Department of Behavioral Neurosciences (KAG), Oregon Health and Science University, and the Oregon National Primate Research Center, Portland, Oregon; Department of Psychiatry (HdW), The University of Chicago, Chicago, Illinois; and Department of Pharmacology (ALM), University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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  • A. Leslie Morrow

    1. From the Department of Psychiatry and Bowles Center for Alcohol Studies (PP, TKO, SEA, SCS, ALM), University of North Carolina School of Medicine, Chapel Hill, North Carolina; Department of Behavioral Neurosciences (KAG), Oregon Health and Science University, and the Oregon National Primate Research Center, Portland, Oregon; Department of Psychiatry (HdW), The University of Chicago, Chicago, Illinois; and Department of Pharmacology (ALM), University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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Reprint requests: A. Leslie Morrow, PhD, University of North Carolina School of Medicine, 3027 Thurston-Bowles Building, CB#7178, Chapel Hill, NC 27599-7178; Tel.: +1-919-9667682; Fax: +1-919-9669099; E-mail: morrow@med.unc.edu

Abstract

Background:  Acute ethanol administration increases plasma and brain levels of progesterone and deoxycorticosterone-derived neuroactive steroids (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP) and (3α,5α)-3,21-dihydroxypregnan-20-one (3α,5α-THDOC) in rats. However, little is known about ethanol effects on GABAergic neuroactive steroids in mice, nonhuman primates, or humans. We investigated the effects of ethanol on plasma levels of 3α,5α- and 3α,5β-reduced GABAergic neuroactive steroids derived from progesterone, deoxycorticosterone, dehydroepiandrosterone, and testosterone using gas chromatography-mass spectrometry.

Methods:  Serum levels of GABAergic neuroactive steroids and pregnenolone were measured in male rats, C57BL/6J and DBA/2J mice, cynomolgus monkeys, and humans following ethanol administration. Rats and mice were injected with ethanol (0.8 to 2.0 g/kg), cynomolgus monkeys received ethanol (1.5 g/kg) intragastrically, and healthy men consumed a beverage containing 0.8 g/kg ethanol. Steroids were measured after 60 minutes in all species and also after 120 minutes in monkeys and humans.

Results:  Ethanol administration to rats increased levels of 3α,5α-THP, 3α,5α-THDOC, and pregnenolone at the doses of 1.5 g/kg (+228, +134, and +860%, respectively, p < 0.001) and 2.0 g/kg (+399, +174, and +1125%, respectively, p < 0.001), but not at the dose of 0.8 g/kg. Ethanol did not alter levels of the other neuroactive steroids. In contrast, C57BL/6J mice exhibited a 27% decrease in serum 3α,5α-THP levels (p < 0.01), while DBA/2J mice showed no significant effect of ethanol, although both mouse strains exhibited substantial increases in precursor steroids. Ethanol did not alter any of the neuroactive steroids in cynomolgus monkeys at doses comparable to those studied in rats. Finally, no effect of ethanol (0.8 g/kg) was observed in men.

Conclusions:  These studies show clear species differences among rats, mice, and cynomolgus monkeys in the effects of ethanol administration on circulating neuroactive steroids. Rats are unique in their pronounced elevation of GABAergic neuroactive steroids, while this effect was not observed in mice or cynomolgus monkeys at comparable ethanol doses.

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