Research reportThe activation of adenosine monophosphate-activated protein kinase in rat hippocampus contributes to the rapid antidepressant effect of ketamine

•The down-regulation of the phosphorylated form of AMPK is observed in the depressed rats.•Ketamine could reserves this down-regulation in the depressed rats, along with a rapid antidepressant effect during FST.•BDNF is involved in the rapid antidepressant effect of ketamine, and maybe partly through the activation of AMPK.•The phosphorylated form of mTOR is not the direct mechanism underlying the rapid antidepressant effect of ketamine.

Recent studies have shown a rapid, robust, and lasting antidepressant effect of ketamine that makes ketamine a promising antidepressant drug. However, the mechanisms underlying this rapid antidepressant effect remain incompletely understood. The goal of the present study was to determine whether adenosine monophosphate-activated protein kinase (AMPK) was involved in ketamine's rapid antidepressant effect during the forced swimming test (FST). In the first stage of experiment, a lower level of phosphorylated form of AMPK (p-AMPK) in the hippocampus and a longer immobility time were observed in the depressed rats during FST; whereas ketamine reversed these changes at 30 min after the administration. In the second stage of experiment, we observed that, ketamine up-regulated the levels of p-AMPK and brain-derived neurotrophic factor (BDNF) in the hippocampus of the depressed rats. Moreover, AMPK agonist strengthened the antidepressant effect of ketamine with an up-regulation of BDNF, while AMPK antagonist attenuated the antidepressant effect of ketamine with a down-regulation of BDNF. In conclusion, our results suggest that the activation of AMPK in rat hippocampus is involved in the procedure of ketamine exerting rapid antidepressant effect through the up-regulation of BDNF.