Chronic mild stress paradigm as a rat model of depression: facts, artifacts, and future perspectives

Abstract

Rationale The chronic mild stress (CMS) paradigm was first described almost 40 years ago and has become a widely used model in the search for antidepressant drugs for major depression disorder (MDD). It has resulted in the publication of almost 1700 studies in rats alone. Under the original CMS procedure, the expression of an anhedonic response, a key symptom of depression, was seen as an essential feature of both the model and a depressive state. The prolonged exposure of rodents to unpredictable/uncontrollable mild stressors leads to a reduction in the intake of palatable liquids, behavioral despair, locomotor inhibition, anxiety-like changes, and vegetative (somatic) abnormalities. Many of the CMS studies do not report these patterns of behaviors, and they often fail to include consistent molecular, neuroanatomical, and physiological phenotypes of CMS-exposed animals. Objectives To critically review the CMS studies in rats so that conceptual and methodological flaws can be avoided in future studies. Results Analysis of the literature supports the validity of the CMS model and its impact on the field. However, further improvements could be achieved by (i) the stratification of animals into ‘resilient’ and ‘susceptible’ cohorts within the CMS animals, (ii) the use of more refined protocols in the sucrose test to mitigate physiological and physical artifacts, and (iii) the systematic evaluation of the non-specific effects of CMS and implementation of appropriate adjustments within the behavioral tests. Conclusions We propose methodological revisions and the use of more advanced behavioral tests to refine the rat CMS paradigm, which offers a valuable tool for developing new antidepressant medications.

Hippocampal Over-Expression of Cyclooxygenase-2 (COX-2) Is Associated with Susceptibility to Stress-Induced Anhedonia in Mice

“…Previous studies with CMS variants stratifying mice for their susceptibility to stressinduced anhedonia showed that it can be associated with expression changes of several molecular and cellular markers of inflammation that are not displayed by resilience to anhedonic animals [22,95,[103][104][105]. For example, CMS-exposed susceptible-to anhedonia-mice revealed significant elevations of COX-1 and IDO expression in the midbrain raphe region, suggesting a possible interaction of neuroinflammation with altered 5-HT transmissionrelation mechanisms [95].…”

“…The remaining animals were considered as non-anhedonic (resilient to stress-induced anhedonia). Applied criterion of anhedonia was based on our previous results, which demonstrated that mice with a sucrose preference ≤65% showed a depressive-like syndrome, consisting in increased floating and decreased exploration, whereas stressed mice with a sucrose preference above this value did not display this behavioral phenotype [22,92,127].…”

“…Mice that had undergone stress but maintained a sucrose preference of >65% were defined as resilient. Other conditions of the test were applied as described elsewhere [22,89,92].…”

“…Many treatment options based on other mechanisms have been proposed, with targets ranging from neurotrophin-and immune-related molecules, to neurodevelopmental, glutamatergic, GABAergic, metabolic mechanisms, and more recently, gut microbiota [18]. The need for a new mechanistic framework for treating MDD is urgently required, but it has been challenging, as translation from clinically relevant animal models to clinical application has been problematic [19][20][21][22]. Among the novel compounds with antidepressant activities, the use of anti-inflammatory drugs, targeting low-level inflammation, a well-established feature of MDD [23][24][25][26][27], might be of particular value owing to the longestablished clinical experience with these widely prescribed drugs [28].…”

“…In this model, the anhedonic (susceptible) state in stressed mice is defined by a decrease in sucrose preference that is not exhibited by non-stressed control animals; typically, it is not displayed by all stressed mice. As such, the non-anhedonic (resilient) mice can be regarded as an internal control for the effects of stress that are not related to depressive-like changes [22,88,92].…”