Jiang Xi, Lin Qian, Xu Lexing, Chen Ziwei, Yan Qizhi, Chen Lei, Yu Xuefeng
Department of Pharmacy, Zhejiang Pharmaceutical College, Ningbo, China.
Mingzhou Hospital, Zhejiang University, Hangzhou, China.
Front Cell Neurosci. 2020 Feb 11;14:11. doi: 10.3389/fncel.2020.00011. eCollection 2020.
Our study was designed to investigate whether the indoleamine-2,3-dioxygenase (IDO)-mediated kynurenine/tryptophan (KYN/TRP) pathway participates in the development of emotional deficits from ethanol addiction/withdrawal mice.
The expression of proinflammatory factors, including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), was tested by enzyme-linked immunosorbent assay (ELISA). The IDO levels in the hippocampus, cerebral cortex, and amygdala were measured by polymerase chain reaction (PCR) and western blot, and the neurotransmitters were tested by high performance liquid chromatography (HPLC). Emotional deficits of mice were evaluated by behavioral tests.
Expression levels of inflammatory factors (TNF-α, IL-1β, and IL-6) were increased in mice after 4 weeks of alcohol exposure. As for indoleamine 2,3-dioxygenase (IDO) expression, only the subtype IDO1 was found to increase at both mRNA level and protein level in all the tested brain regions of ethanol addiction/withdrawal mice. In behavioral tests, mice exposed to alcohol showed gradually declined memory function accompanied by anxiety-like and depressive-like behaviors. Meanwhile, increased expression of KYN, decreased expression of 5-HT, and abnormal expression of 3-HK and KA were found in the hippocampus, cerebral cortex, and amygdala of ethanol addiction/withdrawal mice. Interestingly, the IDO1 inhibitor, 1-methyl-L-tryptophan (1-MT), reversed all above alterations induced by ethanol in mice.
Our results suggested that the TRP/KYN pathway, medicated by IDO1, in the hippocampus, cerebral cortex, and amygdala, plays an important role in the development of emotional deficits caused by ethanol addiction and withdrawal.
本研究旨在调查吲哚胺-2,3-双加氧酶（IDO）介导的犬尿氨酸/色氨酸（KYN/TRP）途径是否参与乙醇成瘾/戒断小鼠情绪缺陷的发展。
通过酶联免疫吸附测定（ELISA）检测促炎因子的表达，包括肿瘤坏死因子α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）。通过聚合酶链反应（PCR）和蛋白质印迹法测量海马体、大脑皮层和杏仁核中的IDO水平，并用高效液相色谱法（HPLC）检测神经递质。通过行为测试评估小鼠的情绪缺陷。
酒精暴露4周后，小鼠体内炎症因子（TNF-α、IL-1β和IL-6）的表达水平升高。至于吲哚胺2,3-双加氧酶（IDO）的表达，在乙醇成瘾/戒断小鼠的所有测试脑区中，仅发现亚型IDO1在mRNA水平和蛋白质水平均增加。在行为测试中，暴露于酒精的小鼠表现出记忆功能逐渐下降，并伴有焦虑样和抑郁样行为。同时，在乙醇成瘾/戒断小鼠的海马体、大脑皮层和杏仁核中发现KYN表达增加、5-HT表达降低以及3-HK和KA表达异常。有趣的是，IDO1抑制剂1-甲基-L-色氨酸（1-MT）逆转了乙醇在小鼠中诱导的所有上述变化。
我们的结果表明，海马体、大脑皮层和杏仁核中由IDO1介导的TRP/KYN途径在乙醇成瘾和戒断引起的情绪缺陷发展中起重要作用。
