组蛋白去乙酰化酶（HDAC）诱导杏仁核中的组蛋白修饰：在快速耐受乙醇的抗焦虑作用中起作用。
Histone deacetylases (HDAC)-induced histone modifications in the amygdala: a role in rapid tolerance to the anxiolytic effects of ethanol.
机构信息
Department of Psychiatry, University of Illinois at Chicago, USA.
出版信息
Alcohol Clin Exp Res. 2012 Jan;36(1):61-71. doi: 10.1111/j.1530-0277.2011.01581.x. Epub 2011 Jul 25.
BACKGROUND
Rapid tolerance to the anxiolytic effects of ethanol appears to be an important factor in the development of alcoholism. Here, we investigated the involvement of amygdaloid histone deacetylases (HDAC)-induced epigenetic changes in rapid ethanol tolerance (RET).
METHODS
RET in rats was induced by 2 ethanol injections administered 24 hours apart. Both ethanol-tolerant and control rats were treated with the HDAC inhibitor, trichostatin A (TSA), and anxiety-like behaviors were measured. HDAC activity, histone (H3 and H4) acetylation, and neuropeptide Y (NPY) expression in the amygdala of these rats were also measured.
RESULTS
A single ethanol exposure was able to produce an anxiolytic response, inhibit amygdaloid HDAC activity, and increase both histone acetylation and NPY expression (mRNA and protein levels) in the central nucleus of amygdala (CeA) and medial nucleus of amygdala (MeA) of rats. In contrast, 2 exposures of the same dose of ethanol (24 hours apart) neither elicited a similar anxiolytic response nor modulated HDAC activity, histone acetylation, or NPY expression in the amygdala. However, exposure to a higher dose of ethanol on the second day was able to produce an anxiolytic response and also inhibit amygdaloid HDAC activity. TSA treatment caused the reversal of RET by inhibiting HDAC activity, thereby increasing histone acetylation and NPY expression in the CeA and MeA.
CONCLUSIONS
Cellular tolerance to the initial acute ethanol-induced inhibition of HDAC activity and the subsequent upregulation of histone acetylation and NPY expression in the amygdala may be involved in the mechanisms underlying rapid tolerance to the anxiolytic effects of ethanol.
背景
乙醇的抗焦虑作用迅速耐受似乎是酒精中毒发展的一个重要因素。在这里，我们研究了杏仁核组蛋白去乙酰化酶（HDAC）诱导的表观遗传变化在快速乙醇耐受（RET）中的作用。
方法
通过 24 小时间隔给予 2 次乙醇注射来诱导大鼠的 RET。用 HDAC 抑制剂曲古抑菌素 A（TSA）处理乙醇耐受和对照大鼠，并测量其焦虑样行为。还测量了这些大鼠杏仁核中的 HDAC 活性、组蛋白（H3 和 H4）乙酰化和神经肽 Y（NPY）表达。
结果
单次乙醇暴露就能产生抗焦虑反应，抑制杏仁核 HDAC 活性，并增加杏仁核中央核（CeA）和杏仁核内侧核（MeA）中的组蛋白乙酰化和 NPY 表达（mRNA 和蛋白水平）。相比之下，24 小时间隔给予相同剂量的乙醇两次既不能引起类似的抗焦虑反应，也不能调节杏仁核中的 HDAC 活性、组蛋白乙酰化或 NPY 表达。然而，第二天接触更高剂量的乙醇就能产生抗焦虑反应，并抑制杏仁核中的 HDAC 活性。TSA 处理通过抑制 HDAC 活性导致 RET 逆转，从而增加 CeA 和 MeA 中的组蛋白乙酰化和 NPY 表达。
结论
细胞对初始急性乙醇诱导的 HDAC 活性抑制和随后的组蛋白乙酰化和 NPY 表达上调的耐受可能参与了乙醇抗焦虑作用迅速耐受的机制。
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