Cyclical administration of corticosterone results in aggravation of depression-like behaviors and accompanying downregulations in reelin in an animal model of chronic stress relevant to human recurrent depression.

Depression is recognized as a highly chronic and recurrent disorder. Each successive episode increases susceptibility to future relapses. The current study aimed to develop an animal model of chronic stress relevant to human recurrent depression in order to examine possible neurobiological mechanisms behind this increased vulnerability. We hypothesized that rats with a prior depression-like episode would be sensitized to subsequent stress, developing depression-like behaviors in response to shorter glucocorticoid exposures. Rats were given corticosterone (CORT) or vehicle injections for one, two, or three 21-day cycles, followed by recovery periods. A series of behavioural assessments were conducted at specific time points after CORT treatment or the recovery period. After behavioral testing, the rats were sacrificed for immunohistochemical analyses of the extracellular matrix protein reelin, which is involved in regulating neural plasticity and is decreased in the hippocampus of depression patients. We found that repeated and cyclic exposure to high levels of CORT escalated depression-like behavior (i.e., forced swim test, sucrose preference test) without altering general locomotor activity (i.e., open field test). Changes in depression-like behaviors were accompanied by cumulative and persistent decreases in reelin-positive cells in the dentate gyrus subgranular zone. These data support the idea of an exacerbation of behavioral and neurochemical alterations with recurrent episodes, which highlights the importance of early therapeutic interventions.

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 40mg/kg) or vehicle for two cycles (21days 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.