Neuroactive steroid stereospecificity of ethanol-like discriminative stimulus effects in monkeys

Kathleen (Kathy) Grant, Christa Helms, Laura S M Rogers, Robert H. Purdy

    Research output: Contribution to journalArticle

    27 Citations (Scopus)

    Abstract

    Positive modulation of GABAA and antagonism of N-methyl-D-aspartate receptors mediate the discriminative stimulus effects of ethanol. Endogenous neuroactive steroids produce effects similar to ethanol, suggesting that these steroids may modulate ethanol addiction. The four isomers of the functional esters at C-3 of the 3-hydroxy metabolites of 4-pregnene-3,20-dione (progesterone) [allopregnanolone (3α,5α-P), pregnanolone (3α,5β-P), epiallopregnanolone (3β,5α-P), and epipregnanolone (3β,5β-P)], a synthetic analog of steroids modified by endogenous sulfation [pregnanolone hemisuccinate (3α,5β-P HS)], and a structurally similar, adrenally derived steroid [3α-hydroxy-5- androstan-17-one (3α,5α-A, androsterone)] were assessed for ethanol-like discriminative stimulus effects at 30 or 60 min after administration in male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) trained to discriminate 1.0 or 2.0 g/kg ethanol (i.g.) with a 30-min pretreatment interval. The 3α-hydroxysteroids completely substituted for ethanol (80% of cases), whereas the 3β-hydroxysteroids and 3α,5β-P HS rarely substituted for ethanol (6% of cases). There were no sex differences. Compared with monkeys trained to discriminate 2.0 g/kg ethanol, 3α,5β-P and 3α,5α-A substituted more potently in monkeys trained to discriminate 1.0 g/kg ethanol. Compared with the 5β-reduced isomer (3α,5β-P), the 5α isomer of pregnanolone (3α,5α-P) substituted for ethanol with 3 to 40-fold greater potency but was least efficacious in female monkeys trained to discriminate 2.0 g/kg ethanol. The data suggest that the discriminative stimulus effects of lower doses (1.0 g/kg) of ethanol are mediated to a greater extent by 3α,5β-P- and 3α,5α-A-sensitive receptors compared with higher doses (2.0 g/kg). Furthermore, the discriminative stimulus effects of ethanol appear to be mediated by activity at binding sites that are particularly sensitive to 3α,5α-P.

    Original languageEnglish (US)
    Pages (from-to)354-361
    Number of pages8
    JournalJournal of Pharmacology and Experimental Therapeutics
    Volume326
    Issue number1
    DOIs
    StatePublished - Jul 2008

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    Haplorhini
    Ethanol
    Steroids
    Pregnanolone
    Hydroxysteroids
    Macaca fascicularis
    Androsterone
    N-Methyl-D-Aspartate Receptors
    Sex Characteristics
    Progesterone
    Binding Sites

    ASJC Scopus subject areas

    • Pharmacology

    Cite this

    Neuroactive steroid stereospecificity of ethanol-like discriminative stimulus effects in monkeys. / Grant, Kathleen (Kathy); Helms, Christa; Rogers, Laura S M; Purdy, Robert H.

    In: Journal of Pharmacology and Experimental Therapeutics, Vol. 326, No. 1, 07.2008, p. 354-361.

    Research output: Contribution to journalArticle

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    abstract = "Positive modulation of GABAA and antagonism of N-methyl-D-aspartate receptors mediate the discriminative stimulus effects of ethanol. Endogenous neuroactive steroids produce effects similar to ethanol, suggesting that these steroids may modulate ethanol addiction. The four isomers of the functional esters at C-3 of the 3-hydroxy metabolites of 4-pregnene-3,20-dione (progesterone) [allopregnanolone (3α,5α-P), pregnanolone (3α,5β-P), epiallopregnanolone (3β,5α-P), and epipregnanolone (3β,5β-P)], a synthetic analog of steroids modified by endogenous sulfation [pregnanolone hemisuccinate (3α,5β-P HS)], and a structurally similar, adrenally derived steroid [3α-hydroxy-5- androstan-17-one (3α,5α-A, androsterone)] were assessed for ethanol-like discriminative stimulus effects at 30 or 60 min after administration in male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) trained to discriminate 1.0 or 2.0 g/kg ethanol (i.g.) with a 30-min pretreatment interval. The 3α-hydroxysteroids completely substituted for ethanol (80{\%} of cases), whereas the 3β-hydroxysteroids and 3α,5β-P HS rarely substituted for ethanol (6{\%} of cases). There were no sex differences. Compared with monkeys trained to discriminate 2.0 g/kg ethanol, 3α,5β-P and 3α,5α-A substituted more potently in monkeys trained to discriminate 1.0 g/kg ethanol. Compared with the 5β-reduced isomer (3α,5β-P), the 5α isomer of pregnanolone (3α,5α-P) substituted for ethanol with 3 to 40-fold greater potency but was least efficacious in female monkeys trained to discriminate 2.0 g/kg ethanol. The data suggest that the discriminative stimulus effects of lower doses (1.0 g/kg) of ethanol are mediated to a greater extent by 3α,5β-P- and 3α,5α-A-sensitive receptors compared with higher doses (2.0 g/kg). Furthermore, the discriminative stimulus effects of ethanol appear to be mediated by activity at binding sites that are particularly sensitive to 3α,5α-P.",
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