Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication.
Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication.
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DOI：
10.1038/s42255-021-00357-z
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发表时间：
2021-03
影响因子：
20.8
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Jin S;Cao Q;Yang F;Zhu H;Xu S;Chen Q;Wang Z;Lin Y;Cinar R;Pawlosky RJ;Zhang Y;Xiong W;Gao B;Koob GF;Lovinger DM;Zhang L
酒精是世界上使用最广泛的精神活性物质之一。乙醇代谢产物，如乙酸盐，被认为主要是乙醇被肝醛脱氢酶2(ALDH2)分解的结果，有助于酒精的行为影响和酒精中毒。在这里，我们表明ALDH2在小鼠小脑的星形胶质细胞中表达，星形胶质细胞ALDH2的乙醇代谢介导了与乙醇中毒相关的行为效应。我们发现，ALDH2在特定脑区的星形胶质细胞中表达，在小鼠小脑中，ALDH2需要星形细胞而不是肝细胞来产生乙醇衍生的乙酸乙酯。小脑星形胶质细胞ALDH2介导了小剂量乙醇引起的GABA水平升高、紧张性抑制增强以及平衡和协调技能的损害。因此，星形细胞ALDH2以特定于大脑区域的方式控制酒精代谢物的产生、细胞和行为影响。我们的数据表明，星形细胞ALDH2是大脑中一个重要的、但以前未被认识到的靶点，它可以改变酒精的药代动力学，并有可能治疗酒精使用障碍。
Alcohol is among the most widely used psychoactive substances worldwide. Ethanol metabolites such as acetate, thought to be primarily the result of ethanol breakdown by hepatic aldehyde dehydrogenase 2 (ALDH2), contribute to alcohol’s behavioural effects and alcoholism. Here, we show that ALDH2 is expressed in astrocytes in the mouse cerebellum and that ethanol metabolism by astrocytic ALDH2 mediates behavioural effects associated with ethanol intoxication. We show that ALDH2 is expressed in astrocytes in specific brain regions and that astrocytic, but not hepatocytic, ALDH2 is required to produce ethanol-derived acetate in the mouse cerebellum. Cerebellar astrocytic ALDH2 mediates low-dose ethanol-induced elevation of GABA levels, enhancement of tonic inhibition and impairment of balance and coordination skills. Thus, astrocytic ALDH2 controls the production, cellular and behavioural effects of alcohol metabolites in a brain-region-specific manner. Our data indicate that astrocytic ALDH2 is an important, but previously under-recognized, target in the brain to alter alcohol pharmacokinetics and potentially treat alcohol use disorder.
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影响因子：
13.8
作者：
Cui C;Koob GF
通讯作者：
Koob GF
影响因子：
24.5
作者：
Gao Y;Zhou Z;Ren T;Kim SJ;He Y;Seo W;Guillot A;Ding Y;Wu R;Shao S;Wang X;Zhang H;Wang W;Feng D;Xu M;Han E;Zhong W;Zhou Z;Pacher P;Niu J;Gao B
通讯作者：
Gao B
DOI：
10.1016/j.jmr.2008.11.001
发表时间：
2009-02
期刊：
Journal of magnetic resonance (San Diego, Calif. : 1997)
影响因子：
--
作者：
Deelchand DK;Nelson C;Shestov AA;Uğurbil K;Henry PG
通讯作者：
Henry PG
影响因子：
8
作者：
Cinar, Resat;Iyer, Malliga R.;Kunos, George
通讯作者：
Kunos, George
影响因子：
--
作者：
Lackey, Elizabeth P;Heck, Detlef H;Sillitoe, Roy V
通讯作者：
Sillitoe, Roy V