The resident-intruder model: a platform for in-depth study of novel molecules with antidepressant activity

Introduction: The aim of the study was to investigate the features of the resident-intruder paradigm as a basic translational method for in-depth evaluation of antidepressant activity of new compounds using the example of 3-ethoxythietane-1,1-dioxide (3ETD), which has antidepressant activity. Materials and Methods: A depressive-like state in white non-inbred rats (intruders) was modeled by long-term (24-day) exposure to chronic social stress (CSS) during interaction with residents. Intruders were divided into 4 experimental groups (n=6). Intruders of the CSS and CSS+3ETD groups interacted with residents daily for 10 min from Day 0 to Day +23, 30 min after intraperitoneal administration of 3ETD (2 mg/kg, 3ETD, CSS+3ETD groups) or saline (Vehicle and CSS groups). At the end of the experiment, the behavior of intruders of all groups was studied in the forced swimming test (FST, Day +23), open field test, and elevated plus maze test (Day +24). Intruders’ body weight and food consumption were measured daily. After euthanasia (Day +24), the weight coefficients of internal organs were calculated and the level of apoptosis markers/regulators in the rat hippocampus was determined immunohistochemically. Results and Discussion: CSS induced a state similar to asthenic depression in intruders: it increased immobility time in FST, the duration of passive behaviors (including submissive), while the duration of active behaviors (defensive, exploratory, social) decreased. 3ETD eliminated these manifestations, exerting an antidepressant effect: it reduced the despair behavior in FST, enhanced motor activity, social and exploratory behavior of intruders, stimulated active defense and reduced passive defense during contact with residents, as well as reduced apoptosis in the hippocampus of intruders, exhibiting neuroprotective properties. Conclusion: The resident-intruder model allows modeling in rats a condition similar to the human asthenic depression and demonstrating the antidepressant effect of novel molecules, as was shown on the 3ETD example when administered at a dose of 2 mg/kg/day intraperitoneally.