We studied the effects of long-term (i.e. 4 weeks) voluntary exercise on the hypothalamic-pituitary-adrenocortical (HPA) axis in male mice. Voluntary exercise was provided by giving mice access to a running wheel in which they indeed ran for about 4 km/day. Exercising mice showed similar body weights as control animals, but presented less abdominal fat, lighter thymuses and heavier adrenal glands. Exercise resulted in asymmetric structural changes in the adrenal glands. Whereas control mice had larger left than right adrenals, this condition was abolished in exercising animals, mainly due to enlargement of the right adrenal cortex. Tyrosine hydroxylase mRNA expression in the adrenal medullas of exercising mice was increased. In exercising mice, early morning baseline plasma ACTH levels were decreased, whereas plasma corticosterone levels at the start of the dark phase were twice as high as those in control animals. To forced swimming and restraint stress, exercising mice responded with higher corticosterone levels, but similar ACTH levels than the control animals. However, if exposed to a novel environment, then exercising mice presented decreased ACTH responses. Interestingly, exercising mice showed a decreased corticosterone response to novelty only when the novel environment contained a functioning running wheel. Glucocorticoid receptor levels were unchanged, whereas mineralocorticoid receptor levels were decreased in hippocampus of exercising animals. Corticotropin-releasing factor (CRF) mRNA levels in the paraventricular nucleus (PVN) were lower in exercising mice.

Thus, voluntary exercise results in complex, adaptive changes at various levels within the HPA axis as well as in sympathoadrenomedullary and limbic/neocortical afferent control mechanisms. These changes seem to underlie the differerential responsiveness of the HPA axis to physical vs. emotional challenges.