Exercise-associated changes in the corticosterone response to acute restraint stress: evidence for increased adrenal sensitivity and reduced corticosterone response duration

Abstract

Exercise promotes stress resistance and is associated with reduced anxiety and reduced depression in both humans and in animal models. Despite the fact that dysfunction within the hypothalamic pituitary adrenal (HPA) axis is strongly linked to both anxiety and depressive disorders, the evidence is mixed as to how exercise alters the function of the HPA axis. Here we demonstrate that 4 weeks of voluntary wheel running was anxiolytic in C57BL/6J mice and resulted in a shorter time to peak corticosterone (CORT) and a more rapid decay of CORT following restraint stress. Wheel running was also associated with increased adrenal size and elevated CORT following systemic administration of adrenocorticotropic hormone. Finally, the HPA-axis response to peripheral or intracerebroventricular administration of dexamethasone did not suggest that wheel running increases HPA-axis negative feedback through GR-mediated mechanisms. Together these findings suggest that exercise may promote stress resilience in part by insuring a more rapid and shortened HPA response to a stressor thus affecting overall exposure to the potentially negative effects of more sustained HPA-axis activation.

Figure 1

Mean startle amplitude (arbitrary unit±SEM) during the 4-week wheel-running period in Experiment 1. Running mice demonstrated reduced startle amplitude compared with baseline on days 14 and 28 of wheel access. ***p<0.001 in comparison with respective test day 0.

Figure 2

Mean plasma corticosterone concentrations (ng/ml±SEM) during restraint stress procedure. Running mice demonstrated an elevated response compared with sedentary animals at 20 min, and also returned to baseline more rapidly. **p<0.01 running in comparison with sedentary at time 20. ^##p<0.01 sedentary time 120 in comparison with sedentary time 0.

Figure 3

(a) Adrenal and (b) thymus weights following 28 days of wheel running (mg±SEM). Total and right adrenal weights (normalized to body weight) were elevated in running mice compared with sedentary controls. Thymus weights were similar in running and sedentary mice. *p<0.05 in comparison with sedentary animals.

Figure 4

(a) ZT12 and (b) ZT13 corticosterone samples following 14 and 28 days of wheel running (ng/ml±SEM). Corticosterone at the onset of the active phase did not differ between running and sedentary mice at any sample point.

Figure 5

Mean plasma corticosterone (ng/ml±SEM) response following ip dexamethasone administration in running and sedentary mice following 28 days of wheel access. Plasma corticosterone was reduced similarly in running and sedentary mice at the highest dose of dexamethasone (0.05 mg/kg). Administration of an intermediate dose of dexamethasone (0.025 mg/kg) did not produce divergent results (inset). ***p<0.001 in comparison with respective 0 mg/kg dose.

Figure 6

Mean plasma corticosterone (ng/ml±SEM) response following ICV dexamethasone administration in running and sedentary mice following 28 days of wheel access. Dexamethasone 2 ng resulted in reduced corticosterone in running and sedentary mice. Administration of an intermediate dose of dexamethasone (750 ng/ml) did not produce divergent results (inset). *p<0.05, **p<0.01 in comparison with respective 0 ng dose.

Figure 7

Mean plasma corticosterone (ng/ml±SEM) response following ACTH administration in running and sedentary mice. Adrenal sensitivity was similar following 50 μg/kg ACTH administration. In contrast, running animals demonstrated enhanced sensitivity to ACTH after administration of 5 μg/kg ACTH. *p<0.05 running in comparison with sedentary at 5 μg/kg dose.