Finn D A, Gallaher E J, Crabbe J C
Portland Alcohol Research Center, Research Service, Veterans Affairs Medical Center and Department of Behavioral Neuroscience, Oregon Health Sciences University, Portland, OR 97201, USA.
J Pharmacol Exp Ther. 2000 Jan;292(1):394-405.
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.
孕酮代谢物3α-羟基-5α-孕烷-20-酮(3α,5α-P或别孕烯醇酮)是γ-氨基丁酸A(GABA(A))受体的强效正性调节剂。尽管有充分文献记载,长期给予乙醇(EtOH)会对苯二氮䓬类药物和GABA在GABA(A)受体上的正性调节作用产生交叉耐受性,但最近的研究结果表明,在EtOH戒断期间,对3α,5α-P的敏感性会增强。此外,对EtOH戒断严重程度不同(DBA/2 >> C57BL/6)的未接触过EtOH的近交系小鼠,对3α,5α-P的行为敏感性也有显著差异。因此,本研究旨在确定C57BL/6(B6)和DBA/2(D2)小鼠在EtOH戒断期间对3α,5α-P的几种药理作用是否会有不同的敏感性。雄性小鼠暴露于EtOH蒸汽或空气中72小时。在从EtOH戒断期间,给动物注射3α,5α-P(0、3.2、10或17 mg/kg腹腔注射),并在高架十字迷宫中测试其活动和抗焦虑作用、肌肉松弛、共济失调以及戊四氮后的惊厥保护作用。在EtOH戒断期间,B6小鼠对3α,5α-P的抗惊厥作用的敏感性增强,但D2小鼠没有。相反,在EtOH戒断的B6和D2小鼠中,对3α,5α-P的肌肉松弛作用的敏感性降低,并且有迹象表明在EtOH戒断期间B6小鼠对3α,5α-P的抗焦虑作用的敏感性降低。这些结果表明,在EtOH戒断期间对3α,5α-P的抗惊厥作用的敏化并不适用于所有基因型,也不适用于3α,5α-P的所有药理作用。