Role of hippocampal p11 in the sustained antidepressant effect of ketamine in the chronic unpredictable mild stress model.

K Hashimoto,J-J Yang,J-C Shen,Z-Q Zhou,C Yang,H-L Sun,X-M Wang,G-F Zhang

doi:10.1038/tp.2016.21

Abstract

Although ketamine shows a rapid and sustained antidepressant effect, the precise mechanisms underlying its effect are unknown. Recent studies indicate a key role of p11 (also known as S100A10) in depression-like behavior in rodents. The present study aimed to investigate the role of p11 in the antidepressant-like action of ketamine in chronic unpredictable mild stress (CUMS) rat model. The open-field test, forced swimming test and sucrose preference test were performed after administration of ketamine (10 mg kg−1) or a combination of ketamine and ANA-12 (a tropomyosin-related kinase B (TrkB) antagonist; 0.5 mg kg−1). The lentivirus vector for p11 was constructed to knock down the hippocampal expression of p11. In the CUMS rats, ketamine showed a rapid (0.5 h) and sustained (72 h) antidepressant effect, and its effect was significantly blocked by co-administration of ANA-12. Furthermore, ketamine significantly increased the reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of CUMS rats, whereas ketamine did not affect the expression of p11 in CUMS rats 0.5 h after administration. In addition, ketamine significantly increased the reduced ratio of p-TrkB/TrkB in the hippocampus by CUMS rats, and its effect was also blocked by ANA-12. Moreover, the reduced expression of BDNF and p11 in the hippocampus of CUMS rats was significantly recovered to control levels 72 h after ketamine administration. Interestingly, knockdown of hippocampal p11 caused increased immobility time and decreased sucrose preference, which were not improved by ketamine administration. These results suggest that p11 in the hippocampus may have a key role in the sustained antidepressant effect of ketamine in the CUMS model of depression.

Highlights

Depression is one of the most common psychiatric disorders affecting nearly 20% of the population worldwide, and more than half of the suicides are accompanied by depression.[1,2,3,4,5] Antidepressants such as selective serotonin reuptake inhibitors (5hydroxytryptamine, 5-HT) and noradrenaline reuptake inhibitors are the clinically prescribed drugs for the treatment of depression
We found that the hippocampal levels of proBDNF and tropomyosin-related kinase B (TrkB) had no significant difference among groups, while the levels of brain-derived neurotrophic factor (BDNF) and p-TrkB/TrkB ratio in the hippocampus of chronic unpredictable mild stress (CUMS) rats were increased at 0.5 h after ketamine administration, indicating that the rapid antidepressant effect of ketamine may be mediated by the stimulation of BDNF– TrkB signaling in the hippocampus
The expressions of proBDNF in the hippocampus from CUMS rats treated with saline, ketamine or a combination of ketamine and ANA-12 had no significant differences compared with the control rats

Summary

Introduction

Depression is one of the most common psychiatric disorders affecting nearly 20% of the population worldwide, and more than half of the suicides are accompanied by depression.[1,2,3,4,5] Antidepressants such as selective serotonin reuptake inhibitors (5hydroxytryptamine, 5-HT) and noradrenaline reuptake inhibitors are the clinically prescribed drugs for the treatment of depression. It takes several weeks for these drugs to exert the antidepressant effects; their remission rates are only approximately 40%.4,6. A number of studies have shown that a single subanesthetic dose of ketamine, a noncompetitive N-methyl-D-aspartate antagonist, produces rapid and sustained antidepressant effects in animal models[7,8,9] and in treatment-resistant patients with major depressive disorder and bipolar disorder.[10,11,12,13] Several molecular mechanisms, neural circuits and signal transduction pathways have been involved in the mechanism of ketamine’s antidepressant effect; the precise mechanisms underlying its antidepressant effect remain largely to be determined.[14,15,16,17,18,19]

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