Concordance and incongruence in preclinical anxiety models: systematic review and meta-analyses

Rodent defense behavior assays have been widely used as preclinical models of anxiety to study possibly therapeutic anxiety-reducing interventions. However, some proposed anxiety-modulating factors—genes, drugs and stressors—have had discordant effects across different studies. To reconcile the effect sizes of purported anxiety factors, we conducted systematic review and meta-analyses of the literature on ten anxiety-linked interventions, as examined in the elevated plus maze, open field and light-dark box assays. Diazepam, 5-HT1A receptor gene knockout and overexpression, SERT gene knockout and overexpression, pain, restraint, social isolation, corticotropin-releasing hormone and Crhr1 were selected for review. Eight interventions had statistically significant effects on rodent anxiety, while Htr1a overexpression and Crh knockout did not. Evidence for publication bias was found in the diazepam, Htt knockout, and social isolation literatures. The Htr1a and Crhr1 results indicate a disconnect between preclinical science and clinical research. Furthermore, the meta-analytic data confirmed that genetic SERT anxiety effects were paradoxical in the context of the clinical use of SERT inhibitors to reduce anxiety. Highlights Meta-analysis shows eight rodent anxiety factors have at least moderate effects. Publication bias affects four of the anxiety interventions. Preclinical rodent anxiety results appear disconnected from clinical efforts. Serotonin transporter gene lesion effects are paradoxical with reuptake inhibitors clinical use.