Influence of gender on chronic ethanol-induced alterations in GABAA receptors in rats
Influence of gender on chronic ethanol-induced alterations in GABAA receptors in rats
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DOI：
10.1016/s0006-8993(98)00357-6
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发表时间：
1998-06-15
期刊：
影响因子：
2.9
通讯作者：
Morrow, AL
中科院分区：
文献类型：
--
作者：
Devaud, LL;Fritschy, JM;Morrow, AL
慢性乙醇暴露引起的乙醇依赖与GABA（A）受体的神经适应有关，表现为各种行为、受体反应性和亚单位基因表达的改变。本研究探讨了酒精依赖的影响，在雌性大鼠与以前的研究在我们的实验室使用雄性大鼠进行比较。我们发现，乙醇依赖导致不同的影响GABA（A）受体基因表达的雌性大鼠大脑皮层相比，乙醇依赖的雄性大鼠。值得注意的是，慢性乙醇消耗没有改变乙醇依赖性雌性大鼠皮层中GABA（A）受体α 1亚基肽水平，与先前观察到的乙醇依赖性雄性大鼠皮层中α 1亚基表达的降低相反。乙醇依赖性对额外GABA（A）受体亚单位肽水平（α 4、β 2/3和γ 2）的影响在雌性和雄性大鼠皮质之间相似，但不完全相同。当在实验中直接比较时，雄性和雌性大鼠具有相似的基线荷包牡丹碱癫痫发作阈值，并且在乙醇戒断期间显示出相似的癫痫发作易感性增加。乙醇戒断雌性大鼠对地西泮的抗惊厥作用具有交叉耐受性，与乙醇戒断雄性大鼠的结果相似。与对照动物相比，乙醇戒断雌性大鼠显示神经活性类固醇THDOC（3 α，21-二羟基-5 α-葡聚糖-20-酮）的抗惊厥作用呈剂量依赖性增强。这一发现与先前在戒断乙醇的雄性和雌性大鼠中观察到的对3 α，5 α-THP（3 α-羟基-5 α-葡聚糖-20-酮）抗惊厥作用的敏感性增加相似。此外，低剂量给药THDOC升高乙醇戒断雌性大鼠的癫痫发作阈值，但不升高雄性大鼠的癫痫发作阈值，这表明乙醇戒断雌性大鼠比乙醇戒断雄性大鼠对这种神经类固醇的抗惊厥作用更敏感。这些发现表明性别对乙醇依赖引起的GABA（A）受体适应性的影响。然而，差异改变的生理结果尚不清楚。综上所述，这些研究表明，除了对GABA（A）受体基因表达的影响外，其他机制也参与了乙醇依赖和戒断的介导。(C)1998 Elsevier Science B. V.保留所有权利。
Ethanol dependence, arising from chronic ethanol exposure, is associated with neuroadaptations of GABA(A) receptors, evidenced by alterations in various behaviors, receptor responsiveness and subunit gene expression. The present studies explored the effects of ethanol dependence in female rats for comparison with previous studies in our laboratory using male rats. We found that ethanol dependence resulted in differential effects on GABA(A) receptor gene expression in female rat cerebral cortex compared to ethanol dependent male rats. Notably, chronic ethanol consumption did not change GABA(A) receptor alpha 1 subunit peptide levels in ethanol dependent female rat cortex, in contrast to previously observed decreases in alpha 1 subunit expression in ethanol dependent male rat cortex. The effects of ethanol dependence on additional GABA(A) receptor subunit peptide levels (alpha 4, beta 2/3 and gamma 2) were similar, but not identical, between female and male rat cortex. When directly compared within the experiment, male and female rats had similar baseline bicuculline seizure thresholds and displayed a similar increase in seizure susceptibility during ethanol withdrawal. Ethanol withdrawn female rats were cross tolerant to the anticonvulsant effects of diazepam, similar to the findings in ethanol withdrawn male rats. Ethanol withdrawn female rats showed a dose-dependent enhancement of the anticonvulsant effect of the neuroactive steroid, THDOC (3 alpha,21-dihydroxy-5 alpha-pregnan-20-one) compared to control animals. This finding is similar to previous observations of increased sensitivity to the anticonvulsant effect of 3 alpha,5 alpha-THP (3 alpha-hydroxy-5 alpha-pregnan-20-one) in ethanol withdrawn male and female rats. In addition, low dose administration of THDOC elevated seizure thresholds in ethanol withdrawn female but not male rats, suggesting that ethanol withdrawn female rats were more responsive to the anticonvulsant effects of this neurosteroid than were ethanol withdrawn male rats. These findings show that gender impacts on adaptations in GABA(A) receptors elicited by ethanol dependence. However, the physiological outcomes of the differential alterations are not clear. Taken together, these studies suggest that additional mechanisms, beyond effects on GABA(A) receptor gene expression are involved in the mediation of ethanol dependence and withdrawal. (C) 1998 Elsevier Science B.V. All rights reserved.