Activation of PI3 K/Akt/GSK3β signaling is necessary for the antidepressant effects of ammoxetine in the forced swimming test and learned helpless test in mice

Currently, accumulating studies indicated that upregulation of glycogen synthase kinase-3β （GSK3β） played an important role in depression pathogenesis. Our previous study demonstrated that ammoxetine, a novel se- rotonin and norepinephrine uptake inhibitor, displayed antidepressant activity more potent and faster than existing antidepressants, which may be clue to the increasing of hippocampal inhibitory serine-phosphorylation of glycogen synthase kinase-3 （GSK3）. The present study was to evaluate whether activation of PI3K/Akt signaling, one of the most important pathways regulating the phosphorylation of GSK3β, was required for ammoxetine induced antide- pressant effects and upregulation of pGSK3β. Behavioral results indicated that acute oral administration of ammoxe- tine at 10 mg/kg produced robust antidepressant effects in the forced swimming test and learned helpless test in mice, which were blocked totally by phosphatidylinositol （PI3）-kinase （PI3K） inhibitor LY294002. Then, West- ern blot results demonstrated that ammoxetine induced increasing of GSK3 β phosphorylation and activation of PI3 K/ Akt signaling can also be antagonized at the same testing time points by LY294002. These findings suggest that ac- tivation of PI3 K/Akt/GSK3[3 signaling is pivotal and necessary for the antidepressant effects of ammoxetine in the forced swimming test and learned helpless test in mice.