The World Health Organization has found mood disorders such as anxiety and depression to be a major contributor to disability and loss of years of health in women and in men . Stressful experiences are implicated in the pathogenesis of mood disorders, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a key feature of depression in particular (reviewed in [2–6]). Clinical research indicates that adolescence is a time of increased risk for mood disorders (reviewed in [7, 8]). Changes in the reactivity of the stress systems during times of biological transitions, such as those occurring in the nervous system and gonadal systems during adolescence, are proposed to underlie the increased vulnerability .
The use of animal models, though not without limitations, is recognized as an important approach to understanding mood disorders [10, 11]. Animal models of depression based on environmental stress (repeated stress exposures administered by the experimenter) have high face and construct validity . Until recently, however, the focus has been on stressors in perinatal life or in adulthood rather than in adolescence . Limitations of many animal models of environmental stress include the lack of control over individual differences and variation in procedures from laboratory to laboratory, which lead to inconsistencies in the literature (reviewed in [14, 15]). These limitations may be especially relevant in investigations of adolescent rats, given the sensitivity of gonadal maturation to environmental factors, the ongoing development of the HPA axis, and the relatively short time frame in which adolescent development occurs . One classification system for adolescence (a transitional period with no clear 'onset' or 'offset') involves three stages, a prepubescence/early adolescence period from postnatal days 21 (when rats are typically weaned in the laboratory) to 34, a mid-adolescence period from postnatal days 34 to 46 (time in which most rats first exhibit the physical markers of puberty, such as vaginal opening and balanopreputial separation), and a late adolescence period from postnatal days 46 to 59 [16–18].
The effects of chronic or repeated stress in humans and in animal models are mediated primarily by the prolonged elevations of glucocorticoids (cortisol in humans, corticosterone in rodents) that are the endpoint of activation of the HPA axis [19, 20]. Thus, repeated administration of exogenous corticosterone has been proposed as an effective means of circumventing some of the limitations of animal models of chronic stress exposures (reviewed in ). Although there is much evidence to indicate that repeated treatment with corticosterone produces reliable changes in a variety of depressive-like behaviors (reviewed in ), this approach has yet to be explored in adolescence. One exception is a study of a low dose of corticosterone (20 mg/ml) administered in the drinking water for 2 months (early adolescence into adulthood), which was found to decrease depression-like behavior in male mice . Thus, more studies are required to assess the use of exogenous corticosterone as an animal model using higher doses and within a timeframe limited to adolescence.
Our laboratory has used a social instability stress model in rats to investigate the consequences of exposure to stressors in mid-adolescence (daily 1 h isolation and change of cage partner from postnatal days 30 to 45) (reviewed in ). Although social instability stress in adolescence produces lasting changes in neurogenesis and decrements in performance of hippocampal-dependent tasks (for example, [23, 24]), effects on anxiety-like and depressive behavior have been modest [25, 26], perhaps because of habituation of corticosterone release to the repeated stress procedures in male rats . Thus, in the present experiments, we investigated the effects of repeated administration of exogenous corticosterone over the same timeframe as our adolescent social instability procedure on anxiety-like and depressive behavior. In experiment 1, we used a 40 mg/kg injection of corticosterone and in experiment 2 we used a 400 mg/ml dose administered in the drinking water; both doses and administration procedures have been used extensively with adult rats (for example, injection [28–30] and in water [31–33]). Vehicle and no treatment controls were included in both experiments, and an adult treatment comparison group was included in experiment 2. In both experiments, 24 h after the last treatment day, anxiety-like behavior was evaluated using the elevated plus maze and after another 24 h, depressive behavior was evaluated using the forced swim test, both well validated measures (reviewed in [34, 35]). In experiment 2, blood samples were obtained at timepoints after the end of the forced swim test to evaluate treatment effects on stress-induced corticosterone release. The aim of the experiments was to assess the potential of exogenous corticosterone as a model for adolescent mood disorders. The main hypothesis of both experiments was that chronic treatment with exogenous corticosterone in adolescence would increase anxiety-like and depressive behavior in rats.