Development and evaluation of an adolescent chronic restraint stress (aCRS) protocol to model adult depression in female rats / by Meghan Hibicke.
Major depressive disorder (MDD), a mood disorder that disproportionately affects women, is often predicated by childhood or adolescent stress. However, females have traditionally been excluded from pharmacological research, and the influence of adolescent stress on depressive-like behaviors has not been widely reported. Additionally, reports correlating adolescent stress with adult depressive-like behaviors have largely neglected to evaluate the effect of common antidepressants. The purpose of this research was to develop and validate an adolescent chronic restraint stress (aCRS) protocol using female rats in order to address the impact of adolescent stress on female adult depressive-like characteristics. During the pilot study, rats were restrained 60 minutes daily for 12 consecutive days beginning in early adolescence, then allowed to mature to adulthood. Control and restrained animals were handled and weighed daily. Behavioral testing included sucrose preference testing (SPT), elevated plus maze (EPM), locomotor activity, novel object recognition (NOR) and object location (OLT), and forced swim tests (FST). Rats were sacrificed immediately following the FST, and trunk blood was collected for corticosterone (CORT) analysis. Four subsequent studies modified the aCRS protocol by increasing the restraint period from 12 to 14 days, using exact-age animals, and by including a treatment period during which antidepressants (fluoxetine and desipramine) or saline were given, and by changing the number and timing of the behavioral assays and sample collections. Additionally, brain-derived neurotrophic factor (BDNF) was assessed. In all studies, aCRS rats displayed significantly increased depressive-like behavior in the FST, but no differences in anxiety-like behaviors or locomotor activity vs control rats. Desipramine, but not fluoxetine, consistently decreased depressive-like behavior in restrained rats. Results of SPT, NOR, OLT, and CORT were inconsistent across experiments. Serum, but not HIP or FCX BDNF, positively correlated with immobility in the FST (a depressive-like behavior), which is not consistent with the literature. In the final experiment, we observed that uterine weights were not normally distributed, with aCRS rats trending low. In conclusion, aCRS elicits increased depressive-like behaviors in adult female rats, without altering anxiety-like behaviors or locomotor activity. Future investigations using aCRS rats should include further evaluation of reproductive hormones and BDNF.