Neurobiology of chronic mild stress: Parallels to major depression

Abstract

The chronic mild (or unpredictable/variable) stress (CMS) model was developed as an animal model of depression more than 20 years ago. The foundation of this model was that following long-term exposure to a series of mild, but unpredictable stressors, animals would develop a state of impaired reward salience that was akin to the anhedonia observed in major depressive disorder. In the time since its inception, this model has also been used for a variety of studies examining neurobiological variables that are associated with depression, despite the fact that this model has never been critically examined to validate that the neurobiological changes induced by CMS are parallel to those documented in depressive disorder. The aim of the current review is to summarize the current state of knowledge regarding the effects of chronic mild stress on neurobiological variables, such as neurochemistry, neurochemical receptor expression and functionality, neurotrophin expression and cellular plasticity. These findings are then compared to those of clinical research examining common variables in populations with depressive disorders to determine if the changes observed following chronic mild stress are in fact consistent with those observed in major depression. We conclude that the chronic mild stress paradigm: (1) evokes an array of neurobiological changes that mirror those seen in depressive disorders and (2) may be a suitable tool to investigate novel systems that could be disturbed in depression, and thus aid in the development of novel targets for the treatment of depression.

Restoration of peripheral V2 receptor vasopressin signaling fails to correct behavioral changes in Brattleboro rats

“…Therefore, it would be worth testing whether during acute stressor exposure somatic-dendritic release of AVP from the SON versus PVN might influence the behavioral response in addition to local signaling (Ebner et al, 2002, Ludwig andLeng, 2006). Anhedonia was suggested to be one of the core symptoms of depression (Di Giannantonio and Martinotti, 2012, Harden et al, 2012, Hill et al, 2012, Warnock et al, 2012. Our experiment investigating anhedonia in KO rats failed to reveal significant differences between the groups.…”

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

“…In the anhedonia model, (Moreau et al, 1992;Moreau, 2002;Holderbach et al, 2007;Hill et al, 2012), the self-stimulation behavior of rats implanted with electrodes in the ventral tegmental area was gradually disrupted by the application of unpredictable CMS. In the vehicle-treated animals, the CMS reduced the self-stimulation over the first 3 weeks, quantitatively expressed in an increased anhedonia index.…”

Salvianolic acid B ameliorates depressive-like behaviors in chronic mild stress-treated mice: involvement of the neuroinflammatory pathway

“…The model provides a natural induction of a chronic depressive-like state that develops gradually over time in response to stress and results in persistent changes in behavior, neurochemistry, and neuroimmune and neuroendocrinological variables resembling those that are observed in depressed patients [28] . This model would therefore be the most valid animal model of depression [29] . C57BL/6 mice respond well to the CMS treatment and are commonly used in antidepressant drug research [30] .…”