Differential change in neuroactive steroid sensitivity during ethanol withdrawal

J Pharmacol Exp Ther. 2000 Jan;292(1):394-405.

Abstract

The progesterone metabolite 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-P or allopregnanolone) is a potent positive modulator of gamma-aminobutyric acid(A) (GABA(A)) receptors. Although it is well documented that chronic ethanol (EtOH) administration produces cross-tolerance to the positive modulatory effect of benzodiazepines and GABA at GABA(A) receptors, recent findings suggest that sensitivity to 3alpha,5alpha-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 3alpha,5alpha-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 3alpha,5alpha-P during EtOH withdrawal. Male mice were exposed to EtOH vapor or air for 72 h. During withdrawal from EtOH, animals were injected with 3alpha,5alpha-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 3alpha,5alpha-P was enhanced during EtOH withdrawal in B6, but not D2 mice. In contrast, sensitivity to the muscle relaxant effects of 3alpha,5alpha-P was reduced in EtOH-withdrawing B6 and D2 mice, with a suggestion of decreased sensitivity to the anxiolytic effect of 3alpha,5alpha-P during EtOH withdrawal in B6. These results suggest that sensitization to the anticonvulsant effect of 3alpha,5alpha-P during EtOH withdrawal does not generalize across all genotypes nor does it generalize to all of the pharmacological effects of 3alpha,5alpha-P.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Inhalation
  • Alcohol Withdrawal Seizures / prevention & control
  • Animals
  • Anticonvulsants / pharmacology*
  • Anxiety / etiology
  • Ataxia / etiology
  • Behavior, Animal / drug effects
  • Dose-Response Relationship, Drug
  • Ethanol / adverse effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Muscle Relaxation / drug effects
  • Pentylenetetrazole / toxicity*
  • Pregnanolone / pharmacology*
  • Radioimmunoassay
  • Species Specificity*
  • Steroids / pharmacology
  • Substance Withdrawal Syndrome / etiology*
  • Substance Withdrawal Syndrome / metabolism*
  • Time Factors

Substances

  • Anticonvulsants
  • Steroids
  • Ethanol
  • Pregnanolone
  • Pentylenetetrazole