Boyce, Zach; Smith, Calvin; Martin, Ashlyn; Ketch, Yuko; Dugan, James; Wright, Cole (Brigham Young University)
Faculty Advisor: Jeffrey, Edwards (Brigham Young University, Physiology and Developmental Biology)
Post-traumatic stress disorder (PTSD) is a complex psychological disorder that affects about 1 of 4 individuals after a stressful/traumatic experience. One common model to induce PTSD in rats is social defeat (SD) combined with chronic light exposure. First, we screened rats for natural anxiety to use in the SD protocol. Next, elevated plus maze (EPM) and light-dark transition (LDT) tests were used to detect anxious behavior after SD. The SD protocol induced significant anxious behavior when compared to controls. Next, we performed long-term potentiation (LTP) field electrophysiology synaptic plasticity physiology experiments in brain slices of the ventral hippocampus (VH) and basolateral amygdala (BLA), regions known to have altered enhanced plasticity in PTSD. SD significantly increased LTP in the VH (~25% greater than control) and BLA (~35% greater than control). To determine whether a prophylactic treatment could prevent the physiological changes of PTSD, we simultaneously administered two drugs at 10 mg/kg doses by intraperitoneal injection one week prior to and for the duration of SD. The first, propranolol, is a beta-adrenergic receptor antagonist, and the second, mifepristone, is a glucocorticoid receptor antagonist; thus, treatment would target the action of stress hormones altered in PTSD. To determine whether a prophylactic treatment could prevent the physiological changes of PTSD, propranolol and mifepristone, antagonists of two stress receptors, were simultaneously administered at 10 mg/kg doses by intraperitoneal (IP) injection one week prior to and for the duration of SThese drugs significantly decreased LTP in the VH and BLA back to near-control levels while SD rats with vehicle injections still had elevated LTP. However, SD drug-treated rats did not show significant reductions in anxious behavior compared to non-injected SD rats and also exhibited significantly more anxious behavior than control rats, suggesting the IP injection induced added stress. Next, we used rtPCR to examine gene expression of drug targets and plasticity markers to determine potential mechanisms for observed LTP changes. In both the VH and BLA, SD was associated with a significant decrease in glucocorticoid and mineralocorticoid receptor expression, which was restored to control levels under drug treatment. Overall, our data suggest that propranolol and mifepristone together may be a potential prophylactic treatment for preventing PTSD through a mechanism likely mediated by glucocorticoid/mineralocorticoid receptors.