Date Published: April 15, 2019
Publisher: Public Library of Science
Author(s): Paul J. Fitzgerald, Jessica Y. Yen, Brendon O. Watson, Kenji Hashimoto.
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.
Major depression, which in many cases is induced by exposure to ongoing marked psychological stress or trauma, is a major public health problem worldwide [1–3]. 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. Infusion of ketamine at a subanesthetic dose indeed has rapid and sustained antidepressant effects in approximately 50% of patients with treatment-resistant depression [6–8]. Interestingly, rodents show a behavioral response to low-dose ketamine on a very similar timescale to that of humans: the response starts within minutes and lasts for days to weeks [9–11]. Translational rodent research originally prompted the discovery of ketamine in human depression , and now reverse translational research helps facilitate further innovation in our understanding of major depression and its pharmacological treatment.
We examined how ketamine effects interacted with stress state by comparing automatically-scored FST and OFT behavior after ketamine dosing in cohorts of unstressed, mildly stressed and UCS-stressed mice. We gave vehicle (VEH– 0.9% saline), ketamine at 10 mg/kg (KET10) and 30 mg/kg (KET30) to separate cohorts of animals in each stress group and compared our nine combinations of stress and dose conditions in FST and OFT at multiple time points (Fig 1). There was a small but statistically significant difference in mouse weight after stress but prior to injection with ketamine: unstressed = 26.2 ± 0.3 g (mean ± SEM), mildly stressed = 24.6 ± 0.4, UCS = 26.1 ± 0.3; p < 0.01. Here we have shown that the effects of ketamine on FST performance depend strongly on the stress state of C57BL/6J mice. Specifically, 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. These data add to a growing literature that suggests ketamine can buffer against chronic stress in C57BL/6J mice, while also providing the (to our knowledge) novel finding that a single injection of this drug can induce depression-like behavior in mice in the absence of significant stress. Below we discuss several topics related to these findings, ranging from clinical relevance to implications for further experiments. Source: http://doi.org/10.1371/journal.pone.0215554