The Mammalian Circadian Clock Exhibits Chronic Ethanol Tolerance and Withdrawal-Induced Glutamate Hypersensitivity, Accompanied by Changes in Glutamate and TrkB Receptor Proteins.
The Mammalian Circadian Clock Exhibits Chronic Ethanol Tolerance and Withdrawal-Induced Glutamate Hypersensitivity, Accompanied by Changes in Glutamate and TrkB Receptor Proteins.
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哺乳动物昼夜节律时钟表现出慢性乙醇的耐受性和戒断诱导的谷氨酸超敏反应，并伴有谷氨酸和TRKB受体蛋白的变化。
DOI：
10.1111/acer.13554
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Prosser RA
中科院分区：
文献类型：
--
作者：
Lindsay JH;Prosser RA
酒精耐受性和戒断诱导效应是DSM-V列出的酒精使用障碍的标准。虽然耐受性和戒断已经研究了几十年，但关于这些不同形式的乙醇（EtOH）诱导的可塑性的机制差异仍然存在不确定性。以前，我们证明了视交叉上核（SCN）的昼夜节律时钟开发急性和快速的耐受乙醇抑制谷氨酸诱导的昼夜节律相移。在这里，我们证明了慢性乙醇耐受性和戒断诱导的谷氨酸超敏性发生在体外，快速耐受性，慢性耐受性和谷氨酸超敏性有不同的细胞变化。我们使用单个单位的细胞外电生理记录，以确定是否慢性耐受EtOH抑制的谷氨酸能相移和撤回诱导的谷氨酸超敏反应的SCN中的发展。我们使用蛋白质印迹法比较磷酸化状态和NMDA受体亚基和相关蛋白的总表达在SCN小鼠暴露于不同的乙醇消耗范式后。在每天4小时的EtOH接触至少8天后形成慢性耐受性，如对EtOH抑制谷氨酸诱导的相移的敏感性降低所示。我们还观察到，谷氨酸诱导的SCN组织中的相移后撤出的敏感性增加。我们证明了NR 2B：NR 2A NMDA受体亚单位表达的比例增加后21天，但不是在10天的乙醇饮用。这种增加在EtOH戒断期间持续，沿着NR 2B Y1472磷酸化、成熟BDNF和磷酸化TrkB的增加。这些结果表明，多种耐受形式和戒断诱导的谷氨酸超敏反应发生在SCN中，这些不同形式的EtOH诱导的可塑性伴随着细胞生理学的不同变化。重要的是，这项研究进一步证明了使用SCN作为模型系统来研究EtOH诱导的可塑性的能力。
Alcohol tolerance and withdrawal-induced effects are criteria for alcohol use disorders listed by the DSM-V. Although tolerance and withdrawal have been studied over many decades, there is still uncertainty regarding mechanistic distinctions that characterize these different forms of ethanol (EtOH)-induced plasticity. Previously, we demonstrated that the suprachiasmatic nucleus (SCN) circadian clock develops both acute and rapid tolerance to EtOH inhibition of glutamate-induced circadian phase shifts. Here, we demonstrate that chronic EtOH tolerance and withdrawal-induced glutamate hypersensitivity occur in vitro, and that rapid tolerance, chronic tolerance, and glutamate hypersensitivity have distinct cellular changes. We use single unit extracellular electrophysiological recordings to determine if chronic tolerance to EtOH inhibition of glutamatergic phase shifts and withdrawal-induced glutamate hypersensitivity develop in the SCN. We use western blotting to compare phosphorylation state and total expression of NMDA receptor subunits and associated proteins in the SCN after mice were exposed to varying EtOH consumption paradigms. Chronic tolerance developed after a minimum of 8 days of 4h/day EtOH access, as indicated by a decreased sensitivity to EtOH inhibition of glutamate-induced phase shifts. We also observed an increased sensitivity to glutamate–induced phase shifts in SCN tissue following withdrawal. We demonstrated an increase in the ratio of NR2B:NR2A NMDA receptor subunit expression after 21 days, but not after 10 days of EtOH drinking. This increase persisted during EtOH withdrawal, along with an increase in NR2B Y1472 phosphorylation, mature BDNF and phosphorylated TrkB. These results demonstrate that multiple tolerance forms and withdrawal-induced glutamate hypersensitivity occur in the SCN and that these different forms of EtOH-induced plasticity are accompanied by distinct changes in cellular physiology. Importantly, this study further demonstrates the power of using the SCN as a model system to investigate EtOH induced plasticity.
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影响因子：
10.6
作者：
Kühlwein, E;Hauger, RL;Irwin, MR
通讯作者：
Irwin, MR
DOI：
10.1016/j.pbb.2017.08.002
发表时间：
2017-09
期刊：
Pharmacology, biochemistry, and behavior
影响因子：
--
作者：
Crabbe JC;Ozburn AR;Metten P;Barkley-Levenson A;Schlumbohm JP;Spence SE;Hack WR;Huang LC
通讯作者：
Huang LC
影响因子：
2.8
作者：
Brager AJ;Prosser RA;Glass JD
通讯作者：
Glass JD
影响因子：
3.4
作者：
Cooper, Joanna M.;Rastogi, Ashutosh;Prosser, Rebecca A.
通讯作者：
Prosser, Rebecca A.
影响因子：
2.7
作者：
Karadayian, Analia G.;Busso, Maria J.;Cutrera, Rodolfo A.
通讯作者：
Cutrera, Rodolfo A.