Differential effects of ethanol on serum GABAergic 3α,5α/ 3α,5β neuroactive steroids in mice, rats, cynomolgus monkeys, and humans

Patrizia Porcu, Todd K. O'Buckley, Sarah E. Alward, Soomin C. Song, Kathleen (Kathy) Grant, Harriet De Wit, A. Leslie Morrow

    Research output: Contribution to journalArticle

    44 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Pages (from-to)432-442
    Number of pages11
    JournalAlcoholism: Clinical and Experimental Research
    Volume34
    Issue number3
    DOIs
    StatePublished - Mar 2010

    Fingerprint

    Macaca fascicularis
    Rats
    Ethanol
    Steroids
    Serum
    Pregnenolone
    Desoxycorticosterone
    Inbred DBA Mouse
    Progesterone
    Pregnanolone
    Plasmas
    Beverages
    Dehydroepiandrosterone
    Inbred C57BL Mouse
    Gas chromatography
    Gas Chromatography-Mass Spectrometry
    Primates
    Haplorhini
    Mass spectrometry
    Testosterone

    Keywords

    • C57BL/6J and DBA/2J Mice
    • Ethanol
    • GABAergic Neuroactive Steroids
    • Humans
    • Nonhuman Primates

    ASJC Scopus subject areas

    • Medicine (miscellaneous)
    • Psychiatry and Mental health
    • Toxicology

    Cite this

    Differential effects of ethanol on serum GABAergic 3α,5α/ 3α,5β neuroactive steroids in mice, rats, cynomolgus monkeys, and humans. / Porcu, Patrizia; O'Buckley, Todd K.; Alward, Sarah E.; Song, Soomin C.; Grant, Kathleen (Kathy); De Wit, Harriet; Leslie Morrow, A.

    In: Alcoholism: Clinical and Experimental Research, Vol. 34, No. 3, 03.2010, p. 432-442.

    Research output: Contribution to journalArticle

    Porcu, Patrizia ; O'Buckley, Todd K. ; Alward, Sarah E. ; Song, Soomin C. ; Grant, Kathleen (Kathy) ; De Wit, Harriet ; Leslie Morrow, A. / Differential effects of ethanol on serum GABAergic 3α,5α/ 3α,5β neuroactive steroids in mice, rats, cynomolgus monkeys, and humans. In: Alcoholism: Clinical and Experimental Research. 2010 ; Vol. 34, No. 3. pp. 432-442.
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    title = "Differential effects of ethanol on serum GABAergic 3α,5α/ 3α,5β neuroactive steroids in mice, rats, cynomolgus monkeys, and humans",
    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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    author = "Patrizia Porcu and O'Buckley, {Todd K.} and Alward, {Sarah E.} and Song, {Soomin C.} and Grant, {Kathleen (Kathy)} and {De Wit}, Harriet and {Leslie Morrow}, A.",
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    T1 - Differential effects of ethanol on serum GABAergic 3α,5α/ 3α,5β neuroactive steroids in mice, rats, cynomolgus monkeys, and humans

    AU - Porcu, Patrizia

    AU - O'Buckley, Todd K.

    AU - Alward, Sarah E.

    AU - Song, Soomin C.

    AU - Grant, Kathleen (Kathy)

    AU - De Wit, Harriet

    AU - Leslie Morrow, A.

    PY - 2010/3

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    N2 - 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.

    AB - 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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    KW - Ethanol

    KW - GABAergic Neuroactive Steroids

    KW - Humans

    KW - Nonhuman Primates

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