Vol. 292, Issue 1, 394-405, January 2000

Differential Change in Neuroactive Steroid Sensitivity during Ethanol Withdrawal¹

Deborah A. Finn, Edward J. Gallaher and John C. Crabbe

Portland Alcohol Research Center, Research Service, Veterans Affairs Medical Center and Department of Behavioral Neuroscience, Oregon Health Sciences University, Portland, Oregon

The progesterone metabolite 3-hydroxy-5-pregnan-20-one (3,5-P or allopregnanolone) is a potent positive modulator of -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 3,5-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 3,5-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 3,5-P during EtOH withdrawal. Male mice were exposed to EtOH vapor or air for 72 h. During withdrawal from EtOH, animals were injected with 3,5-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 3,5-P was enhanced during EtOH withdrawal in B6, but not D2 mice. In contrast, sensitivity to the muscle relaxant effects of 3,5-P was reduced in EtOH-withdrawing B6 and D2 mice, with a suggestion of decreased sensitivity to the anxiolytic effect of 3,5-P during EtOH withdrawal in B6. These results suggest that sensitization to the anticonvulsant effect of 3,5-P during EtOH withdrawal does not generalize across all genotypes nor does it generalize to all of the pharmacological effects of 3,5-P.