Voluntary exercise or systemic propranolol ameliorates stress-related maladaptive behaviors in female rats

Abstract

Many people will experience at least one traumatic event in their lifetime, with up to 20% developing Post-Traumatic Stress Disorder (PTSD) or PTSD-like symptoms. In addition, the likelihood that females will develop PTSD after trauma is more than twice that of males. Despite its prevalence, current treatment strategies for trauma victims are limited and substantial portions of affected individuals remain resistant to treatment, suggesting that additional interventions are necessary. Using an animal model of traumatic stress, the present studies tested the hypothesis that either voluntary exercise and/or administration of the adrenergic beta-receptor antagonist propranolol, would ameliorate stress-related maladaptive behaviors. In Study 1 four groups of female rats were exposed to a sequence of stressors that included anesthesia, restraint, forced swim, exposure to predator scent and fear conditioning. Rats then underwent re-exposure sessions in which stress-related conditioned stimuli were presented. In addition to re-exposure, stressed rats were treated with propranolol (10 mg/kg) and/or given the opportunity to engage in voluntary wheel running intermittently for 4 weeks. Stress-associated maladaptive behavior was assessed using the elevated plus and open field mazes and fear memory tests. Cognitive ability was assessed using a novel odor recognition task. A main effect of exercise on behaviors related to anxiety and resilience was observed, but neither a main effect of propranolol nor a synergistic effect of propranolol and exercise were observed. Neither stress induction nor treatment influenced recognition memory. In contrast, in Study 2 in which the timing and dosage of propranolol (0.25-2.0 mg/kg), and the number and timing of re-exposure sessions were adjusted, propranolol produced both a reduction in anxiety-like behaviors as well as resilience to a subsequent stressor. These results are consistent with the notion that combining re-exposure therapy with additional interventions is beneficial for female trauma victims. Furthermore, the findings support the view that in pre-clinical models, voluntary exercise, which bolsters hippocampal function and propranolol, which affects amygdala-dependent memory reconsolidation and peripheral noradrenergic signaling, can ameliorate stress-related symptoms.