Elsevier

Biological Psychiatry

Volume 79, Issue 9, 1 May 2016, Pages 776-786
Biological Psychiatry

Archival Report
Ketamine as a Prophylactic Against Stress-Induced Depressive-like Behavior

https://doi.org/10.1016/j.biopsych.2015.04.022Get rights and content

Abstract

Background

Stress exposure is one of the greatest risk factors for psychiatric illnesses like major depressive disorder and posttraumatic stress disorder. However, not all individuals exposed to stress develop affective disorders. Stress resilience, the ability to experience stress without developing persistent psychopathology, varies from individual to individual. Enhancing stress resilience in at-risk populations could potentially protect against stress-induced psychiatric disorders. Despite this fact, no resilience-enhancing pharmaceuticals have been identified.

Methods

Using a chronic social defeat (SD) stress model, learned helplessness (LH), and a chronic corticosterone (CORT) model in mice, we tested if ketamine could protect against depressive-like behavior. Mice were administered a single dose of saline or ketamine and then 1 week later were subjected to 2 weeks of SD, LH training, or 3 weeks of CORT.

Results

SD robustly and reliably induced depressive-like behavior in control mice. Mice treated with prophylactic ketamine were protected against the deleterious effects of SD in the forced swim test and in the dominant interaction test. We confirmed these effects in LH and the CORT model. In the LH model, latency to escape was increased following training, and this effect was prevented by ketamine. In the CORT model, a single dose of ketamine blocked stress-induced behavior in the forced swim test, novelty suppressed feeding paradigm, and the sucrose splash test.

Conclusions

These data show that ketamine can induce persistent stress resilience and, therefore, may be useful in protecting against stress-induced disorders.

Section snippets

Mice

Male 129S6/SvEvTac mice were purchased from Taconic (Hudson, New York). CD-1 mice were purchased from Charles River Laboratories (Wilmington, Massachusetts) at 8 to 10 weeks of age and housed individually until the start of SD. The procedures described herein were conducted in accordance with the National Institutes of Health regulations and approved by the Institutional Animal Care and Use Committees of Columbia University and the New York State Psychiatric Institute.

Male C57BL/6NTac mice were

Ketamine Administration Before SD Protects Against the Induction of Depressive-like Behavior

Mice were administered a single injection of saline or ketamine (30 mg kg−1) (Figure 1A). One week later, mice either remained group housed (Ctrl) or underwent SD. After 2 weeks of SD, mice were weighed (Supplemental Figure S2A), and behavior was assessed.

Classically, immobility in the FST has been interpreted as an index of hopelessness or a negative mood (31). Rodents given acute or chronic antidepressants exhibit decreased immobility (32). Here, on day 2 of the FST, there was an overall

Discussion

Here, we have shown that a single injection of ketamine administered before SD protected mice against stress-induced increased immobility time in the FST. Additionally, ketamine protected mice against stress-induced social avoidance of an aggressor mouse. We found that mice administered ketamine before SD were protected against stress-induced depressive-like behavior, but consistent with the literature definition of stress resilience, their behavior in anxiety tests and levels of adult

Acknowledgments and Disclosures

RAB was supported by National Institute of Child Health and Human Development Grant No. T32HD07430. DJD currently was supported by Lundbeck and the Brain & Behavior Research Foundation (formerly National Alliance for Research on Schizophrenia and Depression). The lab UMR S 1178 is funded by Agence Nationale pour la Recherche SAMENTA (Grant No. ANR-12-SAMA-0007). RH was supported by Grant Nos. R37 MH068542 and R01 AG043688, and a Hope for Depression Research Foundation grant. CAD was supported

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