Abstract
Major depression is a stress-linked disease with significant morbidity and the anesthetic drug ketamine is of growing interest in the treatment of depression, since in responsive individuals a single dose has rapid (within hours) antidepressant effects that can be sustained for over a week in some instances. This combination of fast action and a therapeutic effect that lasts far beyond the drug’s half-life points to a unique mechanism of action. In this reverse translational study, we investigate the degree to which ketamine counteracts stress-related depression-like behavioral responses by determining whether it affects unstressed animals similarly to stressed mice. To test this, male C57BL/6J mice were given a single injection of vehicle (0.9% saline; i.p.), 10 mg/kg ketamine, or 30 mg/kg ketamine, and were tested in the forced swim test (FST) 24 hours and 7 days later, as well as in the open field test on the eighth day. Unstressed mice had normal group housing, environmental enrichment, and experimenter pre-handling (5 days), whereas stressed animals were subjected to chronic mild stress (single housing, reduced enrichment and minimal handling), where some mice also had daily two-week unpredictable chronic stress (UCS). We find that ketamine (24 hours post-injection) decreases immobility and increases mobile (swimming) behavior (antidepressant-like effects) in UCS animals but does the opposite in unstressed mice, similar to recent human findings. In summary, these data suggest that chronic psychological stress interacts with ketamine treatment to modulate its effects in the C57BL/6J mouse FST, which reinforces the relevance of this test, and this strain of mice, to human, stress-induced depression.
Highlights
Major depression, which in many cases is induced by exposure to ongoing marked psychological stress or trauma, is a major public health problem worldwide [1,2,3]
We examined how ketamine effects interacted with stress state by comparing automaticallyscored forced swim test (FST) and open field test (OFT) behavior after ketamine dosing in cohorts of unstressed, mildly stressed and unpredictable chronic stress (UCS)-stressed mice
Ketamine (24 hours post-injection) produced depression-like behavior in the FST in unstressed animals, whereas when administered at 30 mg/kg it reduced depression-like behavior in mice subjected to unpredictable chronic stress
Summary
Major depression, which in many cases is induced by exposure to ongoing marked psychological stress or trauma, is a major public health problem worldwide [1,2,3]. Treatment of this debilitating neuropsychiatric disorder is hindered by the delayed response and, in many cases, therapeutic resistance to monoaminergic antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) and tricyclics [4,5]. The response of patients to a single dose of the anesthetic drug ketamine, which gives rapid relief of symptoms in many individuals and outlasts the presence of the drug itself by days to weeks, is fundamentally different from other antidepressive treatments. Stress and ketamine funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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