Adult Rats Exposed to Adolescent Chronic Restraint Stress Display Robust Depressive‐Like Behaviors and Unexpected Responses to Desipramine and Fluoxetine
Authors: Hibicke Meghan , Graham Martha , Hayslett Renee 
Published: November 2023

IntroductionDepression is a mood disorder often predicated by childhood or adolescent stress. Many rodent models of depression utilize neonatal stress to elicit behavioral changes that persist in adulthood, but 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.ObjectiveThe objective of this study is to develop and validate an adolescent chronic restraint stress (aCRS) model of depression in adult female rats.MethodsPilot For the pilot study, 12 adolescent female Sprague‐Dawley rats were shipped post‐natal day (PND) 25–30 and habituated to the colony room for 7 days prior to the experiment. Rats were randomly assigned to Not Restrained (NR, n=6) or Restrained (R, n=6) groups. Beginning PND 36±4, R rats were restrained at random times for 60 min/day for 12 consecutive days. Behavioral testing commenced PND 65±4 and included elevated plus maze (EPM), locomotor activity (LCA), and FST. Experiment 1 Experiment 1 was modified from the pilot in that 27 rats were shipped PND 19, 22, or 23, and randomly assigned to Not Restrained‐Saline (NRSAL, n=6), Restrained‐Saline (RSAL, n=7), Restrained‐Desipramine (RDES, n=7), or Restrained‐Fluoxetine (RFLX, n=7). Restraint began PND 33±1 and lasted 14 consecutive days. Beginning PND 47±1, all animals were given daily subcutaneous injections of 5 mg/kg fluoxetine or desipramine in saline solution, or saline, for 14 days. Behavioral testing commenced PND 61±1 and was preceded by a blood collection that served as a stress challenge. Experiment 2 Experiment 2 was modified from experiment 1 in that 20 rats were shipped PND 19 or 22, group sizes were each n=5, behavioral testing commenced PND 61±1 and did not include EPM. No stress challenge or blood collections were performed. Experiment 3 Experiment 3 was modified from experiment 2 in that 16 rats were shipped PND 23, groups were NRSAL (n=5), RSAL (n=6), or RDES (n=5), restraint began PND 35±1, the final restraint session was followed by 7 days of no stress, injections began PND 56±1, and behavioral testing commenced PND 71±1 and included EPM.ResultsPilot Immobility in the FST was significantly greater in R vs NR rats. EPM and LCA were not different. Experiment 1 Immobility was significantly greater in RSAL vs NRSAL rats due to significantly less swimming. Compared to RSAL, immobility was significantly greater in RDES, but not RFLX rats. EPM and LCA were not different. Experiment 2 Immobility was significantly greater in RSAL vs NRSAL rats due to significantly less swimming and climbing. Compared to RSAL, immobility was significantly less in RDES, but not RFLX rats, due to significantly greater swimming. Both RDES and RFLX showed significantly less locomotor activity vs saline groups, but NRSAL and RSAL were not different from each other. EPM was not different. Experiment 3 Immobility was significantly greater in RSAL vs NRSAL rats due to significantly less swimming. Compared to RSAL, immobility was significantly less in RDES rats due to significantly greater swimming. EPM and LCA were not different.ConclusionThe persistent depressive‐like behaviors elicited by aCRS are reversible with chronic desipramine, but not fluoxetine.Support or Funding InformationMercer University