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Research ArticleNEUROPHARMACOLOGY

Differential Change in Neuroactive Steroid Sensitivity during Ethanol Withdrawal

Deborah A. Finn, Edward J. Gallaher and John C. Crabbe
Journal of Pharmacology and Experimental Therapeutics January 2000, 292 (1) 394-405;
Deborah A. Finn
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Edward J. Gallaher
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John C. Crabbe
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Abstract

The progesterone metabolite 3α-hydroxy-5α-pregnan-20-one (3α,5α-P or allopregnanolone) is a potent positive modulator of γ-aminobutyric acidA (GABAA) receptors. Although it is well documented that chronic ethanol (EtOH) administration produces cross-tolerance to the positive modulatory effect of benzodiazepines and GABA at GABAA receptors, recent findings suggest that sensitivity to 3α,5α-P is enhanced during EtOH withdrawal. In addition, EtOH-naive inbred strains of mice, which differ in EtOH withdrawal severity (DBA/2 ≫ C57BL/6), had marked differences in behavioral sensitivity to 3α,5α-P. Therefore, the present study was conducted to determine whether C57BL/6 (B6) and DBA/2 (D2) mice would be differentially sensitive to several of the pharmacological effects of 3α,5α-P during EtOH withdrawal. Male mice were exposed to EtOH vapor or air for 72 h. During withdrawal from EtOH, animals were injected with 3α,5α-P (0, 3.2, 10, or 17 mg/kg i.p.) and tested for activity and anxiolysis on the elevated plus maze, muscle relaxation, ataxia, and seizure protection following pentylenetetrazol. Sensitivity to the anticonvulsant effect of 3α,5α-P was enhanced during EtOH withdrawal in B6, but not D2 mice. In contrast, sensitivity to the muscle relaxant effects of 3α,5α-P was reduced in EtOH-withdrawing B6 and D2 mice, with a suggestion of decreased sensitivity to the anxiolytic effect of 3α,5α-P during EtOH withdrawal in B6. These results suggest that sensitization to the anticonvulsant effect of 3α,5α-P during EtOH withdrawal does not generalize across all genotypes nor does it generalize to all of the pharmacological effects of 3α,5α-P.

Footnotes

  • Send reprint requests to: Deborah A. Finn, Ph.D., VAMC Research (R & D 12), 3710 SW U.S. Veterans Hospital Rd., Portland, OR 97201. E-mail: finnd{at}ohsu.edu

  • ↵1 This research was supported by U.S. Public Health Service Grant AA10760 from the National Institute on Alcohol Abuse and Alcoholism (to D.A.F. and J.C.C.) and a Merit Review Grant from the Department of Veterans Affairs (to J.C.C.).

  • Abbreviations:
    EtOH
    ethanol
    GABA
    γ-aminobutyric acid
    3α,5α-P
    3α-hydroxy-5α-pregnan-20-one
    B6
    C57BL/6
    D2
    DBA/2
    WSP
    Withdrawal Seizure-Prone
    WSR
    Withdrawal Seizure-Resistant
    BEC
    blood EtOH concentration
    PTZ
    pentylenetetrazol
    MC twitch
    myoclonic twitch
    FF clonus
    face and forelimb clonus
    RB clonus
    running bouncing clonus
    THE
    tonic hindlimb extension
    RIA
    radioimmunoassay
    CORT
    corticosterone
    • Received June 8, 1999.
    • Accepted September 30, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 292 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 292, Issue 1
1 Jan 2000
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Research ArticleNEUROPHARMACOLOGY

Differential Change in Neuroactive Steroid Sensitivity during Ethanol Withdrawal

Deborah A. Finn, Edward J. Gallaher and John C. Crabbe
Journal of Pharmacology and Experimental Therapeutics January 1, 2000, 292 (1) 394-405;

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Research ArticleNEUROPHARMACOLOGY

Differential Change in Neuroactive Steroid Sensitivity during Ethanol Withdrawal

Deborah A. Finn, Edward J. Gallaher and John C. Crabbe
Journal of Pharmacology and Experimental Therapeutics January 1, 2000, 292 (1) 394-405;
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