Dysfunction of the hypothalamic-pituitary-adrenal axis resulting in elevated baseline glucocorticoid concentrations is a hallmark of stress-related human anxiety and affective disorders, including depression. Mice from four replicate lines bred for high voluntary wheel running (HR lines) run almost three times as much as four non-selected control (C) lines, and exhibit two fold elevated baseline circulating corticosterone levels throughout the 24 h cycle. Although elevated baseline CORT may be beneficial for high locomotor activity, chronic elevations can have deleterious effects on multiple systems, and may predispose for affective disorders. Because stressful events often precede a depressive bout, we quantified depressive-like behavior in the forced-swim (FST; generation 41) and tail-suspension tests (TST; generation 47) in HR and C mice that had wheel access for 6 days and then were deprived of wheels on day seven prior to the FST or TST. Male HR spent significantly more time immobile in the FST than C, suggesting that HR males have a predisposition for depression-like behavior. Both male and female HR (generation 43) were more active than same-sex controls in both wheel running and home-cage activity across 22 h (pooling the sexes, HR/C = 2.28 and 2.66, respectively).