Differential change in neuroactive steroid sensitivity during ethanol withdrawal

The progesterone metabolite 3α-hydroxy-5α-pregnan-20-one (3α,5α-P or allopregnanolone) is a potent positive modulator of γ-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 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.