Devaud L L, Fritschy J M, Morrow A L
Bowles Center For Alcohol Studies, Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill 27599, USA.
Brain Res. 1998 Jun 15;796(1-2):222-30. doi: 10.1016/s0006-8993(98)00357-6.
Ethanol dependence, arising from chronic ethanol exposure, is associated with neuroadaptations of GABAA 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 GABAA receptor gene expression in female rat cerebral cortex compared to ethanol dependent male rats. Notably, chronic ethanol consumption did not change GABAA 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 GABAA 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 Ethanol withdrawn female rats were cross tolerant to the anticonvulsant effects of diazepam, similar to the findings in ethanol withdrawn male rats. Ethanol withdrawn female rats showed a dose-dependent enhancement of the anticonvulsant effect of the neuroactive steroid, THDOC (3 alpha,21-dihydroxy-5 alpha-pregnan-20-one)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sensitivity to the anticonvulsant effect of 3 alpha,5 alpha-THP (3 alpha-hydroxy-5 alpha-pregnan-20-one) in ethanol withdrawn male and female rats. In addition, low dose administration of THDOC elevated seizure thresholds in ethanol withdrawn female but not male rats, suggesting that ethanol withdrawn female rats were more responsive to the anticonvulsant effects of this neurosteroid than were ethanol withdrawn male rats.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 GABAA 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 GABAA receptor gene expression are involved in the mediation of ethanol dependence and withdrawal.
慢性乙醇暴露导致的乙醇依赖与GABAA受体的神经适应性变化有关，这在各种行为、受体反应性和亚基基因表达的改变中得到了证实。本研究探讨了乙醇依赖对雌性大鼠的影响，以便与我们实验室之前对雄性大鼠的研究进行比较。我们发现，与乙醇依赖的雄性大鼠相比，乙醇依赖对雌性大鼠大脑皮层中GABAA受体基因表达产生了不同的影响。值得注意的是，与之前观察到的乙醇依赖雄性大鼠皮层中α1亚基表达下降相反，长期摄入乙醇并未改变乙醇依赖雌性大鼠皮层中GABAA受体α1亚基肽水平。乙醇依赖对其他GABAA受体亚基肽水平（α4、β2/3和γ2）的影响在雌性和雄性大鼠皮层中相似，但并不完全相同。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惊厥阈值，并且在乙醇戒断期间惊厥易感性有相似的增加。乙醇戒断的雌性大鼠与乙醇戒断的雄性大鼠一样，对安定的抗惊厥作用产生交叉耐受性。与对照动物相比，乙醇戒断的雌性大鼠显示出神经活性类固醇THDOC（3α,21-二羟基-5α-孕烷-20-酮）的抗惊厥作用呈剂量依赖性增强。这一发现与之前在乙醇戒断的雄性和雌性大鼠中观察到的对3α,5α-THP（3α-羟基-5α-孕烷-20-酮）抗惊厥作用敏感性增加相似。此外，低剂量给予THDOC可提高乙醇戒断雌性大鼠的惊厥阈值，但对雄性大鼠无效，这表明乙醇戒断的雌性大鼠比乙醇戒断的雄性大鼠对这种神经活性类固醇的抗惊厥作用更敏感。这些发现表明，性别会影响乙醇依赖引起的GABAA受体适应性变化。然而，这些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GABAA受体基因表达的影响外，还有其他机制参与介导乙醇依赖和戒断。
