Department of Physiology and Biophysics , University of Illinois at Chicago, Chicago, Illinois.
Center for Alcohol Research in Epigenetics , Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois.
Alcohol Clin Exp Res. 2018 Nov;42(11):2160-2171. doi: 10.1111/acer.13870. Epub 2018 Sep 7.
The ventral tegmental area (VTA) is important for alcohol-related reward and reinforcement. Mouse VTA neurons are hyposensitive to γ-aminobutyric acid (GABA) during ethanol (EtOH) withdrawal, and GABA responsiveness is normalized by in vitro treatment with histone deacetylase inhibitors (HDACi). The present study examined the effect of a systemically administered HDACi, suberanilohydroxamic acid (SAHA) on GABA sensitivity, and related molecular changes in VTA neurons during withdrawal after chronic EtOH intake in rats.
Sprague Dawley male adult rats were fed with Lieber-DeCarli diet (9% EtOH or control diet) for 16 days. Experimental groups included control diet-fed and EtOH diet-fed (0- or 24-hour withdrawal) rats treated with either SAHA or vehicle injection. Single-unit recordings were used to measure the response of VTA neurons to GABA. Immunohistochemistry was performed to examine levels of HDAC2, acetylated histone H3 lysine 9 (acH3K9), and GABA receptor α1 and α5 subunits in the VTA; quantitative polymerase chain reaction was performed to examine the mRNA levels of HDAC2 and GABA receptor subunits.
VTA neurons from the withdrawal group exhibited GABA hyposensitivity. In vivo SAHA treatment 2 hours before sacrifice normalized the sensitivity of VTA neurons to GABA. EtOH withdrawal was associated with increased HDAC2 and decreased acH3K9 protein levels; SAHA treatment normalized acH3K9 levels. Interestingly, no significant change was observed in the mRNA levels of HDAC2. The mRNA levels, but not protein levels, of GABA receptor α1 and α5 subunits were increased during withdrawal.
Withdrawal from chronic EtOH exposure results in a decrease in GABA-mediated inhibition, and this GABA hyposensitivity is normalized by in vivo SAHA treatment. Disruption of signaling in the VTA produced by alteration of GABA neurotransmission could be 1 neuroadaptive physiological process leading to craving and relapse. These results suggest that HDACi pharmacotherapy with agents like SAHA might be an effective treatment for alcoholism.
腹侧被盖区（VTA）在与酒精相关的奖赏和强化中起重要作用。在乙醇（EtOH）戒断期间，小鼠 VTA 神经元对γ-氨基丁酸（GABA）的反应性降低，而体外用组蛋白去乙酰化酶抑制剂（HDACi）处理可使 GABA 反应性正常化。本研究在大鼠慢性 EtOH 摄入后戒断期间，检查了全身性给予 HDACi 琥珀酸酐（SAHA）对 VTA 神经元 GABA 敏感性的影响，以及相关的分子变化。
Sprague Dawley 雄性成年大鼠用 Lieber-DeCarli 饮食（9%EtOH 或对照饮食）喂养 16 天。实验组包括对照饮食喂养和 EtOH 饮食喂养（0 或 24 小时戒断）大鼠，用 SAHA 或载体注射处理。单细胞记录用于测量 VTA 神经元对 GABA 的反应。免疫组织化学用于检测 VTA 中的 HDAC2、组蛋白 H3 赖氨酸 9 乙酰化（acH3K9）和 GABA 受体α1 和α5 亚基的水平；定量聚合酶链反应用于检测 HDAC2 和 GABA 受体亚基的 mRNA 水平。
戒断组的 VTA 神经元表现出 GABA 反应性降低。在处死前 2 小时体内给予 SAHA 治疗可使 VTA 神经元对 GABA 的敏感性正常化。EtOH 戒断与 HDAC2 增加和 acH3K9 蛋白水平降低有关；SAHA 治疗使 acH3K9 水平正常化。有趣的是，HDAC2 的 mRNA 水平没有显著变化。GABA 受体α1 和α5 亚基的 mRNA 水平而不是蛋白水平在戒断期间增加。
慢性 EtOH 暴露戒断导致 GABA 介导的抑制减少，而这种 GABA 反应性降低可通过体内 SAHA 治疗得到正常化。GABA 神经传递改变引起的 VTA 信号转导中断可能是导致渴望和复发的 1 种神经适应性生理过程。这些结果表明，用 SAHA 等 HDACi 药物治疗可能是治疗酒精中毒的有效方法。
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