Cyclical corticosterone administration sensitizes depression-like behavior in rats

Because stress is a significant risk factor for depression, many animal models of depression employ chronic stress as a precipitating event. However, almost without exception, stress-induced animal models of depression focus on a single bout of depression and therefore, they do not provide any means to understand the typical cycling of mood observed in most patients with depression. Here we assessed whether repeated cycles of exposure to the stress hormone corticosterone would sensitize depression-like behavior. Rats were treated with corticosterone (CORT; 20 or 40 mg/kg) or vehicle for two cycles (21 days each), followed by a 21-day recovery period. Depression-like behavior was assessed via repeated forced swim tests (FSTs) in the middle and at the end of each CORT treatment and at the end of each recovery period. Our results showed that CORT administration for two cycles produces increasingly greater effects on depression-like behavior and a decrease in recovery between cycles. Potential confounding effects of body weight and repetitive behavioral testing are considered in the interpretation of these effects. Our approach of using more than one cycle of CORT exposure provides strong face validity as it mimics several aspects of human depression. The use of multiple cycles of CORT exposure may provide a means to study the episode recurrence seen in more than 70% of patients with depression.