Validity of chronic restraint stress for modeling anhedonic-like behavior in rodents: a systematic review and meta-analysis

BACKGROUND: Chronic restraint stress (CRS) is widely used to recapitulate depression phenotypes in rodents but is frequently criticized for a perceived lack of efficacy. The aim of this study was to evaluate anhedonic-like behavior in the CRS model in rodents by performing a meta-analysis of studies that included sucrose preference tests. METHODS: This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. We comprehensively searched for eligible studies published before June 2021 in the PubMed, Embase, Medline, and Web of Science databases. We chose sucrose preference ratio as the indicative measure of anhedonia because it is a core symptom of depression in humans. RESULTS: Our pooled analysis included 34 articles with 57 studies and seven rodent species/strains and demonstrated decreased sucrose preference in the stress group compared with controls. The duration of CRS differentially affected the validity of anhedonic-like behavior in the models. Rats exhibited greater susceptibility to restraint stress than mice, demonstrating inter-species variability. CONCLUSIONS: Our meta-analysis of studies that used the CRS paradigm to evaluate anhedonic-like behavior in rodents was focused on a core symptom of depression (anhedonia) as the main endpoint of the model and identified species-dependent susceptibility to restraint stress.