氯胺酮抑制HCN1离子通道参与抗抑郁作用的研究

发布时间：2018-09-05 19:53

【摘要】：目的探讨超极化激活的环核苷酸门控的离子通道亚型1(HCN1)是否参与了亚麻醉剂量氯胺酮(KET)的抗抑郁作用。方法选择全身HCN1敲除(HCN1-/-)及其相对应的野生型(HCN1+/+)8~12周龄雄性C57BL6小鼠。在行为学实验中,长期低剂量饮水口服皮质酮(CORT)使小鼠产生慢性抑郁状态,采用强迫游泳实验(FST)中小鼠不动时间来评估小鼠抑郁状态。小鼠随机一次性腹腔注射5mg/kg KET(KET组,n=7)或等体积生理盐水(NS组,n=7),并且记录比较4组抑郁小鼠给予注射后30min,24h,7d在强迫游泳实验中的不动时间。另外选取正常HCN1-/-和HCN1+/+小鼠,各小鼠给予腹腔注射5-溴脱氧尿嘧啶核苷(BrdU)后24h,随机一次性腹腔注射5mg/kg KET(KET组,n=5)或等体积生理盐水(NS组,n=5),24h后断头取脑,采用免疫荧光染色,观察4组小鼠海马中BrdU标记的新生神经元的数目。结果 CORT处理前HCN1-/-小鼠的不动时间短于HCN1+/+小鼠(P0.01),抑郁状态较HCN1+/+小鼠轻;CORT处理后各基因型小鼠的不动时间均较基础值增加(P0.01),抑郁状态加重。比较30min内、24h内及7d内不动时间的减小幅度,HCN1+/+KET组在任一时间点均大于其余3组(P0.05),HCN1-/-KET、HCN1+/+NS组及HCN1-/-NS组在上述任一时间段不动时间变化幅度差异均无统计学意义。NS处理后,HCN1-/-小鼠海马中新生神经元数目多于HCN1+/+小鼠(P0.05);HCN1+/+小鼠给予KET 24h后,其海马中新生神经元数目较生理盐水组增多(P0.05),而HCN1-/-小鼠给予KET后,其海马神经元数目与生理盐水组比较,差异无统计学意义。结论KET抗抑郁作用可能是通过抑制HCN1离子通道实现的。
[Abstract]:Objective to investigate whether hyperpolarization-activated cyclic nucleotide-gated ion channel subtype 1 (HCN1) is involved in the antidepressant effect of ketamine (KET). Methods the whole body HCN1 knockout (HCN1-/-) and its corresponding wild type (HCN1 /) 8-week-old male C57BL6 mice were selected. In the behavioral experiment, long-term low-dose drinking of corticosterone (CORT) induced chronic depression in mice, and the immobility time of mice in forced swimming test (FST) was used to evaluate the depressive state of mice. Mice were randomly injected intraperitoneally with 5mg/kg KET (KET group (n = 7) or NS group (n = 7), and the time of immobility in forced swimming test was recorded and compared in the four groups of depression mice 30 minutes after injection for 24 hours and 7 days after injection. In addition, normal HCN1-/- and HCN1 / mice were given intraperitoneal injection of 5-bromodeoxyuridine (BrdU) for 24 hours. The rats were randomly injected intraperitoneally with 5mg/kg KET (KET group (n + 5) or NS group (n ~ (5) for 24 h. The number of BrdU labeled neonate neurons in hippocampus of 4 groups was observed. Results before CORT treatment, the immobility time of HCN1-/- mice was shorter than that of HCN1 / mice (P0.01), and the time of depression was higher than that of HCN1 / mice after mild Cort treatment (P0.01). Comparison of the decrease of fixed time within 24 hours and 7 days in 30min HCN1 / KET group was larger than the other three groups at any time point (P0.05). There was no significant difference between HCN1-r -KETHCN1 / NS group and HCN1-/-NS group in any of the above time periods. NS processing. The number of neonate neurons in hippocampus of HCN1-r-mice was higher than that of HCN1 / mice (P0.05). After 24 hours of KET administration, the number of HCN1 neurons in hippocampus of HCN1-r-mice was higher than that of HCN1 / mice. The number of hippocampal neurons in HCN1-/- mice was higher than that in saline group (P0.05), but the number of hippocampal neurons in HCN1-/- mice was not significantly different from that in saline group. Conclusion the antidepressant effect of KET may be achieved by inhibiting HCN1 ion channel.
【作者单位】：四川大学华西医院麻醉科;华中科技大学协和医院麻醉科;
【基金】：国家自然科学基金项目(No.81171274)资助
【分类号】：R749.4

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