锌剂预处理对丙咪嗪抗抑郁药效的增强作用及其机制OACSTPCD

Objective To investigate the enhancing effect of zinc pretreatment on antidepressant effect of imipra-mine and to explore the underlying mechanism.Methods SD rats were randomly divided into the model group,zinc group,imipramine group,zinc+imipramine group,zinc+H89+imipramine group,and control group.In the model group,zinc group,imipramine group,zinc+imipramine group,zinc+H89+imipramine group,we constructed the learned helplessness depression models by using the electric box;the rats in the control group were also placed in the elec-tric box,but no electric shock was given.After modeling,rats in the model group were intraperitoneally injected with nor-mal saline;rats in the zinc group were intraperitoneally injected with zinc gluconate for 3 consecutive days;rats in the imipramine group were intraperitoneally injected with imipramine as a single dose;rats in the zinc+imipramine group were intraperitoneally injected with zinc gluconate for 3 consecutive days and were given imipramine on the 4th day;rats in the zinc+H89+imipramine group were intraperitoneally injected with zinc gluconate for 3 consecutive days,and were in-jected with H89[protein kinase A(PKA)inhibitor]injection after zinc administration on the first day and were given imip-ramine on the 4th day;rats in the normal control group were injected with normal saline.Depressive behaviors were as-sessed 24 h after the last administration using the shock shuttle-escape test and forced swimming test.Subsequently,the lateral habenular(LHb)was collected to evaluate the expression of cytochrome oxidase and Kir4.1 protein in astrocytes.Results In the forced swimming test,the zinc group,imipramine group,zinc+H89+imipramine group,and LH model group exhibited significantly longer immobility time compared with the control group.Similarly,in the shock shuttle-es-cape test,these groups showed more failure escape time compared with the control group.Notably,the zinc+imipramine group displayed significantly shorter immobility time and fewer failures in both tests compared with the model group,zinc group,imipramine group and zinc+H89+imipramine group(all P<0.01).The expression levels of cytochrome oxidase and Kir4.1 in the zinc group,imipramine group,zinc+H89+imipramine group,and model group were higher than those of the control group,the expression levels of cytochrome oxidase and Kir4.1 in the zinc group,imipramine group,zinc+imipramine group were lower than those of the model group,and the zinc+imipramine group exhibited significantly lower expression levels of cytochrome oxidase and Kir4.1 in comparison with those of the zinc group and imipramine group(all P<0.01).Conclusion Zinc pretreatment can rapidly enhance the antidepressant effects of imipramine.Its mechanism of action may be related to regulating the expression of Kir4.1 and inhibiting the clustered discharge of the LHb,and this effect can be blocked by the PKA inhibitor H89.