Maldonado-Devincci Antoniette M, Kampov-Polevoi Alexander, McKinley Raechel E, Morrow Danielle H, O'Buckley Todd K, Morrow A Leslie
Department of Psychology, North Carolina Agricultural and Technical State University Greensboro, NC, USA.
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill Chapel Hill, NC, USA.
Front Cell Neurosci. 2016 Mar 4;10:40. doi: 10.3389/fncel.2016.00040. eCollection 2016.
The GABAergic neuroactive steroid (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP, allopregnanolone) is decreased in various brain regions of C57BL/6J mice following exposure to an acute stressor or chronic intermittent ethanol (CIE) exposure and withdrawal. It is well established that there are complex interactions between stress and ethanol drinking, with mixed literature regarding the effects of stress on ethanol intake. However, there is little research examining how chronic ethanol exposure alters stress responses. The present work examined the impact of CIE exposure and withdrawal on changes in brain levels of 3α,5α-THP, as well as hormonal and behavioral responses to forced swim stress (FSS). Adult male C57BL/6J mice were exposed to four cycles of CIE to induce ethanol dependence. Following 8 h or 72 h withdrawal, mice were subjected to FSS for 10 min, and 50 min later brains were collected for immunohistochemical analysis of cellular 3α,5α-THP. Behavioral and circulating corticosterone responses to FSS were quantified. Following 8 h withdrawal, ethanol exposure potentiated the corticosterone response to FSS. Following 72 h withdrawal, this difference was no longer observed. Following 8 h withdrawal, stress-exposed mice showed no differences in immobility, swimming or struggling behavior. However, following 72 h withdrawal, ethanol-exposed mice showed less immobility and greater swimming behavior compared to air-exposed mice. Interestingly, cellular 3α,5α-THP levels were increased in the lateral amygdala 8 h and 72 h post-withdrawal in stressed ethanol-exposed mice compared to ethanol-exposed/non-stressed mice. In the paraventricular nucleus of the hypothalamus, stress exposure decreased 3α,5α-THP levels compared to controls following 72 h withdrawal, but no differences were observed 8 h post-withdrawal. There were no differences in cellular 3α,5α-THP levels in the nucleus accumbens shell at either withdrawal time point. These data suggest that there are different mechanisms mediating hormonal, behavioral, and brain responses to stress following CIE exposure. The lateral amygdala appears to be an extremely sensitive brain region exhibiting changes in cellular 3α,5α-THP levels following CIE and exposure to swim stress. It is likely that these changes in cellular 3α,5α-THP levels in the lateral amygdala contribute to the behavioral effects observed following 72 h withdrawal.
γ-氨基丁酸能神经活性甾体（3α,5α）-3-羟基孕烷-20-酮（3α,5α-四氢孕酮，别孕烯醇酮）在C57BL/6J小鼠暴露于急性应激源或慢性间歇性乙醇（CIE）暴露及戒断后，其在各个脑区的水平会降低。应激与乙醇摄入之间存在复杂的相互作用，关于应激对乙醇摄入影响的文献存在分歧。然而，很少有研究探讨慢性乙醇暴露如何改变应激反应。本研究考察了CIE暴露及戒断对3α,5α-四氢孕酮脑内水平变化的影响，以及对强迫游泳应激（FSS）的激素和行为反应。成年雄性C57BL/6J小鼠接受四个周期的CIE以诱导乙醇依赖。在戒断8小时或72小时后，小鼠接受10分钟的FSS，50分钟后收集大脑用于细胞3α,5α-四氢孕酮的免疫组织化学分析。对FSS的行为和循环皮质酮反应进行量化。戒断8小时后，乙醇暴露增强了对FSS的皮质酮反应。戒断72小时后，这种差异不再观察到。戒断8小时后，应激暴露小鼠在不动、游泳或挣扎行为方面没有差异。然而，戒断72小时后，与空气暴露小鼠相比，乙醇暴露小鼠的不动时间减少，游泳行为增加。有趣的是，与乙醇暴露/非应激小鼠相比，应激乙醇暴露小鼠在戒断后8小时和72小时，外侧杏仁核中的细胞3α,5α-四氢孕酮水平升高。在下丘脑室旁核中，戒断72小时后，与对照组相比，应激暴露降低了3α,5α-四氢孕酮水平，但戒断8小时后未观察到差异。在两个戒断时间点，伏隔核壳中的细胞3α,5α-四氢孕酮水平均无差异。这些数据表明，CIE暴露后对应激的激素、行为和脑反应存在不同的介导机制。外侧杏仁核似乎是一个极其敏感的脑区，在CIE和暴露于游泳应激后，其细胞3α,5α-四氢孕酮水平会发生变化。外侧杏仁核中细胞3α,5α-四氢孕酮水平的这些变化可能导致了戒断72小时后观察到的行为效应。
