Differential change in neuroactive steroid sensitivity during ethanol withdrawal

The progesterone metabolite 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha ,5 alpha-P or allopregnanolone) is a potent positive modulator of gamma-ami nobutyric acid(A) (GABA(A)) receptors. Although it is well documented that chronic ethanol (EtOH) administration produces cross-tolerance to the posit ive modulatory effect of benzodiazepines and GABA at GABAA receptors, recen t findings suggest that sensitivity to 3 alpha, 5 alpha-P is enhanced durin g EtOH withdrawal. In addition, EtOH-naive inbred strains of mice, which di ffer in EtOH withdrawal severity (DBA/2 >> C57BL/6), had marked differences in behavioral sensitivity to 3 alpha,5 alpha-P. Therefore, the present stu dy was conducted to determine whether C57BL/6 (B6) and DBA/2 (D2) mice woul d be differentially sensitive to several of the pharmacological effects of 3 alpha,5 alpha-P during EtOH withdrawal. Male mice were exposed to EtOH va por or air for 72 h. During withdrawal from EtOH, animals were injected wit h 3 alpha,5 alpha-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 se izure protection following pentylenetetrazol. Sensitivity to the anticonvul sant effect of 3 alpha,5 alpha-P was enhanced during EtOH withdrawal in B6, but not D2 mice. In contrast, sensitivity to the muscle relaxant effects o f 3 alpha,5 alpha-P was reduced in EtOH-withdrawing B6 and D2 mice, with a suggestion of decreased sensitivity to the anxiolytic effect of 3 alpha,5 a lpha-P during EtOH withdrawal in B6. These results suggest that sensitizati on to the anticonvulsant effect of 3 alpha,5 alpha-P during EtOH withdrawal does not generalize across all genotypes nor does it generalize to all of the pharmacological effects of 3 alpha, 5 alpha-P.