A role of GABAA receptor α1 subunit in the hippocampus for rapid-acting antidepressant-like effects of ketamine
A role of GABAA receptor α1 subunit in the hippocampus for rapid-acting antidepressant-like effects of ketamine
复制标题
海马 GABAA 受体 α1 亚基对氯胺酮快速抗抑郁样作用的作用
DOI：
10.1016/j.neuropharm.2022.109383
复制
发表时间：
2022-12
影响因子：
4.7
通讯作者：
Jian-Jun Yang
中科院分区：
文献类型：
--
作者：
Xiao-Hui Tang;Yu-Gang Diao;Zhuo-Yu Ren;Yan-Yu Zang;Guang-Fen Zhang;Xing-Ming Wang;Gui-Fang Duan;Jin-Chun Shen;Kenji Hashimoto;Zhi-Qiang Zhou;Jian-Jun Yang
氯胺酮可以在难治性抑郁症患者中产生快速起效的抗抑郁作用。虽然大脑中谷氨酸能和GABA能神经传递的改变在抑郁症中起作用，但氯胺酮抗抑郁作用背后的这些神经传递的精确分子机制仍在很大程度上未知。暴露于FSS（强迫游泳应激）的小鼠表现出抑郁样行为，海马中GABA（γ-氨基丁酸）水平下降，但谷氨酸水平不变。氯胺酮增加GABA水平和降低谷氨酸水平的小鼠海马暴露于FSS。GABA水平与抑郁样行为之间存在相关性。此外，氯胺酮可增加GABA能神经元（SAT 1、GAD 67、GAD 65、VGAT和GAT 1）和星形胶质细胞（EAAT 2和GAT 3）上的酶和转运蛋白水平，而不影响GABA能神经元上的酶和转运蛋白（SAT 2、VGluT 1和GABAAR γ2）水平。氯胺酮可使GABA能神经元和星形胶质细胞特异性表达的GABAAR α1亚单位表达减少，GABA能神经元合成代谢增加，星形胶质细胞可塑性改变，ATP含量增加。最后，GABAAR拮抗剂荷包牡丹碱或ATP产生了快速的抗抑郁样作用，而GABAAR激动剂蝇蕈醇预处理阻断了氯胺酮的抗抑郁样作用。此外，药理学激活和抑制GABAAR调节GABA的合成和代谢，以及海马星形胶质细胞的可塑性。目前的数据表明，氯胺酮可以通过下调GABAAR α1，增加GABA，并将GABA转化为ATP，从而增加GABA的合成和星形胶质细胞的可塑性，从而产生快速作用的抗抑郁样作用。
Ketamine can produce rapid-acting antidepressant effects in treatment-resistant patients with depression. Although alterations in glutamatergic and GABAergic neurotransmission in the brain play a role in depression, the precise molecular mechanisms in these neurotransmission underlying ketamine's antidepressant actions remain largely unknown. Mice exposed to FSS (forced swimming stress) showed depression-like behavior and decreased levels of GABA (γ-aminobutyric acid), but not glutamate, in the hippocampus. Ketamine increased GABA levels and decreased glutamate levels in the hippocampus of mice exposed to FSS. There was a correlation between GABA levels and depression-like behavior. Furthermore, ketamine increased the levels of enzymes and transporters on the GABAergic neurons (SAT1, GAD67, GAD65, VGAT and GAT1) and astrocytes (EAAT2 and GAT3), without affecting the levels of enzymes and transporters (SAT2, VGluT1 and GABAAR γ2) on glutamatergic neurons. Moreover, ketamine caused a decreased expression of GABAAR α1 subunit, which was specifically expressed on GABAergic neurons and astrocytes, an increased GABA synthesis and metabolism in GABAergic neurons, a plasticity change in astrocytes, and an increase in ATP (adenosine triphosphate) contents. Finally, GABAAR antagonist bicuculline or ATP exerted a rapid antidepressant-like effect whereas pretreatment with GABAAR agonist muscimol blocked the antidepressant-like effects of ketamine. In addition, pharmacological activation and inhibition of GABAAR modulated the synthesis and metabolism of GABA, and the plasticity of astrocytes in the hippocampus. The present data suggest that ketamine could increase GABA synthesis and astrocyte plasticity through downregulation of GABAAR α1, increases in GABA, and conversion of GABA into ATP, resulting in a rapid-acting antidepressant-like action.This article is part of the Special Issue on ‘Ketamine and its Metabolites’.
登录
查看更多内容
影响因子：
10.6
作者：
Chowdhury, Golam M. I.;Behar, Kevin L.;Cho, William;Thomas, Monique A.;Rothman, Douglas L.;Sanacora, Gerard
通讯作者：
Sanacora, Gerard
影响因子：
4.4
作者：
Eid, Tore;Behar, Kevin;Dhaher, Ronnie;Bumanglag, Argyle V.;Lee, Tih-Shih W.
通讯作者：
Lee, Tih-Shih W.
影响因子：
11
作者：
Milak MS;Proper CJ;Mulhern ST;Parter AL;Kegeles LS;Ogden RT;Mao X;Rodriguez CI;Oquendo MA;Suckow RF;Cooper TB;Keilp JG;Shungu DC;Mann JJ
通讯作者：
Mann JJ
影响因子：
11
作者：
Fava M;Freeman MP;Flynn M;Judge H;Hoeppner BB;Cusin C;Ionescu DF;Mathew SJ;Chang LC;Iosifescu DV;Murrough J;Debattista C;Schatzberg AF;Trivedi MH;Jha MK;Sanacora G;Wilkinson ST;Papakostas GI
通讯作者：
Papakostas GI
DOI：
10.1523/jneurosci.17-08-02921.1997
发表时间：
1997-04
期刊：
The Journal of Neuroscience
影响因子：
--
作者：
B. Moghaddam;Barbara W. Adams;A. Verma;D. Daly
通讯作者：
B. Moghaddam;Barbara W. Adams;A. Verma;D. Daly