Devaud L L, Purdy R H, Morrow A L
Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill 27599-7175, USA.
Alcohol Clin Exp Res. 1995 Apr;19(2):350-5. doi: 10.1111/j.1530-0277.1995.tb01514.x.
Prolonged alcohol consumption leads to the development of tolerance to and dependence on ethanol, resulting in a decreased response to the sedative/hypnotic effects of ethanol, and by negative symptomatology following abrupt termination of use. One symptom associated with ethanol withdrawal in humans, as well as laboratory animals, is enhanced susceptibility to seizures. This study investigated the effects of the neurosteroid, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-5 alpha-THP), on alterations in seizure sensitivity associated with ethanol withdrawal. 3 alpha-5 alpha-THP is a potent anxiolytic and anticonvulsant agent that acts via selective interactions with GABAA receptors. Extensive evidence suggests that some aspects of ethanol dependence and withdrawal are mediated by alterations in GABAA receptor function. Withdrawal from chronic ethanol exposure elicited dramatic increases in seizure susceptibility in male and female rats. Administration of 3 alpha-5 alpha-THP just before seizure threshold determinations blocked the increased seizure susceptibility induced by ethanol withdrawal. Ethanol-withdrawn animals were protected by 3 alpha-5 alpha-THP at a dose that had no effect on control animal seizure thresholds. Moreover, male and female rats displayed differential responses to the seizure-threshold lowering effects of ethanol withdrawal, as well as the protection by 3 alpha-5 alpha-THP pretreatment. These findings suggest that there are gender differences associated both with ethanol withdrawal as well as the protection by 3 alpha-5 alpha-THP in ethanol-dependent rats.
长期饮酒会导致对乙醇产生耐受性和依赖性，从而降低对乙醇镇静/催眠作用的反应，并在突然停止使用后出现负面症状。与人类以及实验动物乙醇戒断相关的一种症状是对癫痫发作的易感性增强。本研究调查了神经甾体3α-羟基-5α-孕烷-20-酮（3α-5α-四氢孕酮）对与乙醇戒断相关的癫痫敏感性改变的影响。3α-5α-四氢孕酮是一种强效抗焦虑和抗惊厥剂，通过与GABAA受体的选择性相互作用发挥作用。大量证据表明，乙醇依赖和戒断的某些方面是由GABAA受体功能的改变介导的。慢性乙醇暴露戒断会使雄性和雌性大鼠的癫痫易感性显著增加。在癫痫阈值测定前给予3α-5α-四氢孕酮可阻断乙醇戒断诱导的癫痫易感性增加。3α-5α-四氢孕酮以对对照动物癫痫阈值无影响的剂量保护乙醇戒断的动物。此外，雄性和雌性大鼠对乙醇戒断降低癫痫阈值的作用以及3α-5α-四氢孕酮预处理的保护作用表现出不同的反应。这些发现表明，在乙醇依赖的大鼠中，乙醇戒断以及3α-5α-四氢孕酮的保护作用都存在性别差异。
