Effects Of AMPK On The Rapid Antidepressant Effect Of Ketamine In Rat

Objective:This research adopted the forced swimming test (FST) to establish the acute depression model. The rats were pretreated with the agonist of adenosine monophosphate-activated protein kinase (AMPK),5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) or the blocker of AMPK, Compound C, to observe the antidepressant effect of ketamine. Detect the expressions of phosphorylation adenosine monophosphate-activated protein kinase (p-AMPK), brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal associated protein (ARC), mammalian target of rapamycin (mTOR) and phosphorylation mammalian target of rapamycin (p-mTOR). The goal of the research was to determine whether AMPK is involved in the antidepressant effect of ketamine and explore the possible mechanism.Methods:Fifty-four healthy adult male Wistar rats, weighing 200-280 g, were divided into 6 groups (n=9 each):saline group (S group), ketamine group (K group), AICAR group (A group), AICAR and ketamine group (AK group), Compound C group (C group), Compound C and ketamine group (CK group). The rats were forced to swim for 15 min, to establish the acute depression model, and 24 hours later, the rats in the six groups were peritoneal injected with the same volume of saline, saline, AICAR (10 mg/kg), AICAR (10 mg/kg), Compound C (1 mg/kg), Compound C (1 mg/kg) separately,30 minutes later, the six groups were peritoneal injected with the same volume of saline, ketamine, saline, ketamine, saline, ketamine separately. Thirty minutes after the drug administration, the rats were forced to swim for 6 min, and recorded the immobility time of rats in the late 5 min. The expressions of p-AMPK, BDNF and ARC were detected by enzyme linked immunosorbent assay (ELISA). The expressions of mTOR and p-mTOR were detected by Western Blot.Results:1. The immobility time of rats in FST:compared with S group, the immobility time in K group, AK group and CK group was reduced significantly (P<0.01); Compared with K group, the immobility time in AK group was reduced significantly, while it was prolonged in CK group (P<0.05).2. The expressions of p-AMPK of rats’hippocampus:compared with S group, the expressions of p-AMPK in K group and AK group were up-regulated (P<0.05).3. The expressions of BDNF of rats’hippocampus:compared with S group, the expressions of BDNF in K group, A group AK and CK group were up-regulated (P<0.05); Compared with K group, the expressions of BDNF in AK group was up-regulated, while it was down-regulated in CK group (P<0.05).4. The expressions of ARC of rats’hippocampus:compared with S group, the expressions of ARC in K group, A group AK and CK group were up-regulated (P<0.05); Compared with K group, the expressions of ARC in AK group was up-regulated (P<0.05).5. The relations between the expressions of BDNF and ARC:the correlation coefficient between the expressions of ARC and BDNF was 0.906 (P<0.001).6. The expressions of p-mTOR and mTOR of rats’hippocampus:the expressions of p-mTOR in K group, AK group, C group and CK group were higher than in S group (P<0.01); Compared with K group, the expression in A group was reduced, while in C group was raised (P<0.05); The differences among the six groups about mTOR expressions had no statistical meaning.Conclusions:Ketamine exerts rapid antidepressant effect during the FST, and it,may be related with the up-regulated expressions of p-AMPK and BDNF; The rats pretreated with the agonist of AMPK, AICAR, strengthens the antidepressant effect of ketamine, while pretreated with the antagonist of AMPK, Compound C, attenuates the antidepressant effect of ketamine; Ketamine up-regulates the expression of BDNF might be partly through activating AMPK, which subsequently up-regulates the expression of ARC.