Stress-sensitive antidepressant-like effects of ketamine in the mouse forced swim test

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.

Ovarian hormones mediate the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-hydroxynorketamine in female mice

“…Previous results have demonstrated that (R,S)-ketamine and (2R,6R)-HNK are rapidacting antidepressants and effective in both sexes (14,15,19). However, this effect is strain-and stress-specific, as has been previously shown by our lab and others (30,31).…”

Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine

“…Our findings that sub-chronic ketamine administration elevates striatal dopamine synthesis capacity, which persists for several days post dosing, suggest that this could contribute to ketamine's antidepressant actions [48]. The majority of pre-clinical studies investigating the antidepressant effects of ketamine used a 10 mg/kg dose of ketamine, but doses as high as 50 mg/kg have also been used to show antidepressant-like effects [105][106][107][108][109][110]. In human studies the optimal therapeutic dose for ketamine is debated, with 0.5 mg/kg having dissociative, psychotomimetic and antidepressant effects [111,112], whilst 0.2 mg/kg is generally considered sub-therapeutic, although one study reported positive therapeutic effects with 0.1 mg/kg [14,111,113].…”

The Dysregulation of the Hypothalamic-pituitary-adrenal Axis in Diet-induced Prediabetic Male Sprague Dawley Rats

“…The immobility of the rodents has been suggested to be an adaptive behaviour rather than a representation of an internal state of defeat leading to psychomotor retardation as seen in humans (65,67). While this is a possibility, there are various studies which have shown the use of this test to be viable in showing the individual rat's coping response to stress (66,68,69). Multiple studies that have investigated antidepressants have shown that the induction of chronic stress in rodents has resulted in the state of defeat which has been likened to psychomotor retardation in humans with depression (66, 68, 69).…”

“…Multiple studies that have investigated antidepressants have shown that the induction of chronic stress in rodents has resulted in the state of defeat which has been likened to psychomotor retardation in humans with depression (66, 68, 69). The use of some of these antidepressants was shown to reduce the immobility of the once immobile rats after treatment by seeing an increase in struggling time (66,68,69). Immobility of the rat, known as a state of defeat, includes very minute movements to remain above water to breathe without the vigorous struggle of trying to escape as seen in the non-prediabetic group with increased struggle time (70).…”