The Mood Stabilizer Lithium Potentiates the Antidepressant-Like Effects and Ameliorates Oxidative Stress Induced by Acute Ketamine in a Mouse Model of Stress
The Mood Stabilizer Lithium Potentiates the Antidepressant-Like Effects and Ameliorates Oxidative Stress Induced by Acute Ketamine in a Mouse Model of Stress
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DOI：
10.1093/ijnp/pyu102
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发表时间：
2015-04-01
影响因子：
4.8
通讯作者：
Chuang, De-Maw
中科院分区：
文献类型：
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作者：
Chiu, Chi-Tso;Scheuing, Lisa;Chuang, De-Maw
背景：有证据表明，雷帕霉素激活的哺乳动物靶标介导氯胺酮快速但短暂的抗抑郁作用，而糖原合酶激酶 3 beta 会抑制该途径。然而，氯胺酮具有相关的拟精神病作用并且滥用风险很高。情绪稳定剂锂是一种糖原合成酶激酶 3 抑制剂，具有很强的抗自杀特性。在这里，我们使用小鼠应激模型来研究辅助锂治疗是否会增强氯胺酮的抗抑郁样作用。方法：小鼠在饮用水中接受慢性束缚应激和长期氯胺酮锂治疗前或后。研究了锂对氯胺酮诱导的抗抑郁样作用、雷帕霉素/脑源性神经营养因子信号通路哺乳动物靶标的激活、氧化应激和小鼠大脑树突棘密度的影响。结果：亚治疗（600 mg/L）锂预处理的小鼠表现出抗抑郁样反应 强迫游泳试验中氯胺酮（2.5 mg/kg，腹腔注射）挑战无效。氯胺酮注射后（1200 mg/L 锂）治疗至少 2 周，单次氯胺酮（50 mg/kg）注射诱导的应激小鼠内侧前额叶皮层的抗抑郁样作用和树突棘密度恢复均得到维持。锂治疗的这些益处与哺乳动物前额皮质中雷帕霉素/脑源性神经营养因子信号通路靶点的激活有关。急性氯胺酮（50 mg/kg）注射还显着增加应激小鼠的脂质过氧化、过氧化氢酶活性和氧化谷胱甘肽水平。值得注意的是，这些氧化应激标记物通过 1200 mg/L 锂的预处理被完全消除。结论：我们的结果提出了一种新的治疗策略，并证明在受益于氯胺酮的患者中使用锂是合理的。
Background: Evidence suggests that mammalian target of rapamycin activation mediates ketamine's rapid but transient antidepressant effects and that glycogen synthase kinase-3 beta inhibits this pathway. However, ketamine has associated psychotomimetic effects and a high risk of abuse. The mood stabilizer lithium is a glycogen synthase kinase-3 inhibitor with strong antisuicidal properties. Here, we used a mouse stress model to investigate whether adjunct lithium treatment would potentiate ketamine's antidepressant-like effects.Methods: Mice received chronic restraint stress and long-term pre- or postketamine lithium treatment in drinking water. The effects of lithium on ketamine-induced antidepressant-like effects, activation of the mammalian target of rapamycin/brain-derived neurotrophic factor signaling pathways, oxidative stress, and dendritic spine density in the brain of mice were investigated.Results: Subtherapeutic (600 mg/L) lithium-pretreated mice exhibited an antidepressant-like response to an ineffective ketamine (2.5 mg/kg, intraperitoneally) challenge in the forced swim test. Both the antidepressant-like effects and restoration of dendritic spine density in the medial prefrontal cortex of stressed mice induced by a single ketamine (50 mg/kg) injection were sustained by postketamine treatment with 1200 mg/L of lithium for at least 2 weeks. These benefits of lithium treatments were associated with activation of the mammalian target of rapamycin/brain-derived neurotrophic factor signaling pathways in the prefrontal cortex. Acute ketamine (50 mg/kg) injection also significantly increased lipid peroxidation, catalase activity, and oxidized glutathione levels in stressed mice. Notably, these oxidative stress markers were completely abolished by pretreatment with 1200 mg/L of lithium.Conclusions: Our results suggest a novel therapeutic strategy and justify the use of lithium in patients who benefit from ketamine.