A role of GABA A receptor α1 subunit in the hippocampus for rapid-acting antidepressant-like effects of ketamine.

Autor: Tang XH; Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China., Diao YG; Department of Anesthesiology, General Hospital of Northern Theater Command, Shenyang, China., Ren ZY; Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China., Zang YY; Minister of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China., Zhang GF; Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China., Wang XM; Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan., Duan GF; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China., Shen JC; Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China., Hashimoto K; Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan., Zhou ZQ; Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China. Electronic address: zq_zhou@163.com., Yang JJ; Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Electronic address: yjyangjj@126.com.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2023 Mar 01; Vol. 225, pp. 109383. Date of Electronic Publication: 2022 Dec 21.
DOI: 10.1016/j.neuropharm.2022.109383
Abstrakt: 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 GABA A R γ2) on glutamatergic neurons. Moreover, ketamine caused a decreased expression of GABA A R 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, GABA A R antagonist bicuculline or ATP exerted a rapid antidepressant-like effect whereas pretreatment with GABA A R agonist muscimol blocked the antidepressant-like effects of ketamine. In addition, pharmacological activation and inhibition of GABA A R 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 GABA A R 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'.
Competing Interests: Declaration of competing interest Dr. Hashimoto is the inventor of filed patent applications on “The use of R-Ketamine in the treatment of psychiatric diseases”, “(S)-norketamine and salt thereof as pharmaceutical”, “R-Ketamine and derivative thereof as prophylactic or therapeutic agent for neurodegeneration disease or recognition function disorder”, “Preventive or therapeutic agent and pharmaceutical composition for inflammatory diseases or bone diseases”, “R-Ketamine and its derivatives as a preventive or therapeutic agent for a neurodevelopmental disorder”, and “Preventive or therapeutic agent and pharmaceutical composition for inflammatory diseases” by the Chiba University. Dr. K. Hashimoto has also received speakers’ honoraria, consultant fee, or research support from Abbott, Boehringer Ingelheim, Daiichi-Sankyo, Meiji Seika Pharma, Seikagaku Corporation, Sumitomo-Pharma, Taisho, Otsuka, Murakami Farm and Perception Neuroscience. Other authors declare no conflict of interest.
(Copyright © 2022. Published by Elsevier Ltd.)
Databáze: MEDLINE
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