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

Abstract

Background Stress exposure is one of the greatest risk factors for psychiatric illnesses like Major Depressive Disorder (MDD) and Post-Traumatic Stress Disorder (PTSD). 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 (K) could protect against depressive-like behavior. Mice were administered a single dose of saline (Sal) or ketamine and then one 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 (Ctrl) mice. Mice treated with prophylactic ketamine were protected against the deleterious effects of SD in the forced swim test (FST) and in the dominant interaction (DI) 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 FST, novelty suppressed feeding (NSF) paradigm, and the sucrose splash test (ST). Conclusions These data show that ketamine can induce persistent stress resilience and, therefore, may be useful in protecting against stress-induced disorders.

Previous Ketamine Produces an Enduring Blockade of Neurochemical and Behavioral Effects of Uncontrollable Stress

“…This is exactly the pattern found here. The PL-to DRN pathway is critical because activation of this pathway inhibits the DRN (Hajó s et al, 1998), and indeed, pharmacological activation of this pathway during IS blocks the behavioral and neurochemical effects of IS (for review, see Maier, 2015). The question here was whether previous ketamine would alter the pattern of IS effects, and we found that previous ketamine produced only one change: now IS activated neurons that project from the PL to the DRN.…”

“…This is consistent with the idea that ketamine acts by altering PL pyramidal cells that can inhibit DRN 5-HT cells, so that now these PL cells become activated by IS. The mechanisms suggested here could be readily applied to the findings by Brachman et al (2015).…”

“…Previous experience with control blocks the effects of subsequent IS because it alters the PL-DRN projecting neurons so that now IS activates these cells, which it would not do without this previous experience (Baratta et al, 2009). A variety of findings suggest that the experience of control alters the PL-DRN projection so that it becomes responsive to uncontrollable stressors by inducing a plasticity process (for review, see Maier, 2015). Thus, mPFC microinjection of protein synthesis inhibitors (Amat et al, 2006), NMDA antagonists , and ERK inhibitors , before the ES experience, all prevent ES-induced blockade of the neurochemical and behavioral effects of IS occurring 7 d later.…”

“…The effectiveness of ketamine in reversing the effects of acute and chronic stressors has also been assessed. With regard to acute stressors, a number of studies have exposed mice and rats to a single session of inescapable shocks (ISs) and examined a number of behavioral con-sequences of the IS anywhere from 1 to 18 d later (Maeng et al, 2008;Beurel et al, 2011;Koike et al, 2011). In all of these studies, ketamine was administered shortly before the behavioral testing rather than before the IS, and the IS-induced changes were reversed.…”

“…To our knowledge, only the recent study by Brachman et al (2015) has dealt with possible prophylactic effects of ketamine. Here we explore this prophylactic phenomenon with a different species and stressor and begin to study the mechanism of prophylaxis.…”