Finn D A, Roberts A J, Lotrich F, Gallaher E J
Research Service, Department of Veterans Affairs Medical Center, Portland, Oregon 97201, USA.
J Pharmacol Exp Ther. 1997 Feb;280(2):820-8.
Recent work found that lower endogenous levels of the gamma-aminobutyric acid-agonist, neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) may be correlated with increased ethanol withdrawal severity in the selectively bred Withdrawal Seizure-Prone and -Resistant mice. The present studies were conducted to determine whether decreased sensitivity to 3alpha,5alpha-THP was correlated with ethanol withdrawal hyperexcitability in another genetic mouse model, namely the C57BL/6 (B6) and DBA/2 (D2) inbred strains. These strains also differ in ethanol withdrawal severity (D2 >> B6). B6 and D2 male mice were injected with 3alpha,5alpha-THP (0-10 mg/kg i.p.) 15 min before the timed tail vein infusion of pentylenetetrazol. B6 mice were more sensitive than D2 animals to the anticonvulsant effect of 3alpha,5alpha-THP. Subsequent studies measured sensitivity to several of the pharmacological effects of 3alpha,5alpha-THP. B6 and D2 male mice were injected with 3alpha,5alpha-THP (0-32 mg/kg) before testing for locomotor activation (total number of entries) and anxiolysis (percent open arm entries) on the elevated plus maze, muscle relaxation (impairment of forelimb grip strength), ataxia (impairment of Rotarod performance) and seizure susceptibility to pentylenetetrazol. B6 mice were more sensitive than D2 animals to the anxiolytic, locomotor stimulant and anticonvulsant effects of 3alpha,5alpha-THP. In contrast, D2 mice were more sensitive than B6 mice to 3alpha,5alpha-THP-induced muscle relaxation and ataxia. Plasma 3alpha,5alpha-THP levels did not differ in the B6 and D2 mice injected with this steroid, suggesting that the strain differences were not pharmacokinetic. Collectively, the results in selectively bred Withdrawal Seizure-Prone and -Resistant mice and B6 and D2 inbred strains suggest that genetic differences in neuroactive steroid sensitivity and biosynthesis may contribute to ethanol withdrawal severity.
最近的研究发现，在选择性培育的易发生戒断性癫痫和抗戒断性癫痫的小鼠中，内源性γ-氨基丁酸激动剂、神经活性甾体3α-羟基-5α-孕烷-20-酮（3α,5α-THP）水平较低可能与乙醇戒断严重程度增加有关。本研究旨在确定在另一种基因小鼠模型，即C57BL/6（B6）和DBA/2（D2）近交系中，对3α,5α-THP敏感性降低是否与乙醇戒断性过度兴奋有关。这些品系在乙醇戒断严重程度上也存在差异（D2 >> B6）。在定时尾静脉注射戊四氮前15分钟，给B6和D2雄性小鼠腹腔注射3α,5α-THP（0 - 10 mg/kg）。B6小鼠比D2小鼠对3α,5α-THP的抗惊厥作用更敏感。随后的研究测量了对3α,5α-THP几种药理作用的敏感性。在高架十字迷宫上测试运动激活（进入总数）和抗焦虑作用（开放臂进入百分比）、肌肉松弛（前肢握力受损）、共济失调（转棒试验表现受损）以及对戊四氮的癫痫易感性之前，给B6和D2雄性小鼠注射3α,5α-THP（0 - 32 mg/kg）。B6小鼠比D2小鼠对3α,5α-THP的抗焦虑、运动刺激和抗惊厥作用更敏感。相比之下，D2小鼠比B6小鼠对3α,5α-THP诱导的肌肉松弛和共济失调更敏感。注射该甾体的B6和D2小鼠血浆3α,5α-THP水平没有差异，这表明品系差异不是药代动力学方面的。总体而言，选择性培育的易发生戒断性癫痫和抗戒断性癫痫的小鼠以及B6和D2近交系的研究结果表明，神经活性甾体敏感性和生物合成的基因差异可能导致乙醇戒断严重程度不同。
