Sex differences in the rapid and the sustained antidepressant-like effects of ketamine in stress-naïve and “depressed” mice exposed to chronic mild stress

Abstract

During the past decade, one of the most striking discoveries in the treatment of major depression was the clinical finding that a single infusion of a sub-anesthetic dose of the N-methyl-d-aspartate receptor antagonist ketamine produces a rapid (i.e. within a few hours) and long-lasting (i.e. up to two weeks) antidepressant effect in both treatment-resistant depressed patients and in animal models of depression. Notably, converging clinical and preclinical evidence support that responsiveness to antidepressant drugs is sex-differentiated. Strikingly, research regarding the antidepressant-like effects of ketamine has focused almost exclusively on the male sex. Herein we report that female C57BL/6J stress-naïve mice are more sensitive to the rapid and the sustained antidepressant-like effects of ketamine in the forced swim test (FST). In particular, female mice responded to lower doses of ketamine (i.e. 3mg/kg at 30 min and 5mg/kg at 24h post-injection), doses that were not effective in their male counterparts. Moreover, tissue levels of the excitatory amino acids glutamate and aspartate, as well as serotonergic activity, were affected in a sex-dependent manner in the prefrontal cortex and the hippocampus, at the same time-points. Most importantly, a single injection of ketamine (10mg/kg) induced sex-dependent behavioral effects in mice subjected to the chronic mild stress (CMS) model of depression. Intriguingly, female mice were more reactive to the earlier effects of ketamine, as assessed in the open field and the FST (at 30 min and 24h post-treatment, respectively) but the antidepressant potential of the drug proved to be longer lasting in males, as assessed in the splash test and the FST (days 5 and 7 post-treatment, respectively). Taken together, present data revealed that ketamine treatment induces sex-dependent rapid and sustained neurochemical and behavioral antidepressant-like effects in stress-naïve and CMS-exposed C57BL/6J mice.

Dipyrone ameliorates behavioural changes induced by unpredictable chronic mild stress: gender differences

“…Increased latency to groom and reduced total grooming time in the sucrose ST is representative of the core symptom of depression, anhedonia. These results show some similarity to earlier results indicating that the antidepressant potential of ketamine was longer lasting in males, as assessed in the ST [38]; however, our ST results contradict other studies that report that either both sexes or only female mice are susceptible to ST. These discrepancies between various studies may be related to strain differences, as mentioned above.…”

Effects of single-dose ketamine infusion on behavioral parameters and neuronal activation in the medial prefrontal cortex of juvenile rats exposed to prenatal stress

“…[54] These results are in agreement with other studies utilizing a 10-or 12-day dosing regimen to establish longer-lasting effects of chronic ketamine on depressive-like activity in the FST. [55,56] In the literature, there are significant dose, gender and strain-dependent differences in the sensitivity to ketamine treatment. For example, Wistar rats are insensitive to the antidepressant-like effects of low dose ketamine (2.5 and 5 mg/kg) in comparison to Wistar-Kyoto rats.…”

“…Although female mice were shown more reactive to the earlier effects of ketamine, the antidepressant potential of this drug was proved to last longer in male animals. [56] A recent clinical study suggested that sex differences in glutamate receptor gene expression might also play a major role in depression and antidepressant efficacy of drugs. [3] In a large cohort of postmortem subjects from MDD patients and controls, more generalized and severe disruption in the regulation of the glutamate receptors were found in females, but more specific alterations were reported in males.…”

Short‐ and long‐term antidepressant effects of ketamine in a rat chronic unpredictable stress model

“…Each rat was first placed in the central zone of the EPM with its head oriented to the closed arm. The rat was allowed to freely explore the maze for 5 min as described previously (Franceschelli, Sens, Herchick, Thelen, & Pitychoutis, 2015;Suo et al, 2013) …”