Acute exposure to a novel stressor further reduces the habituated corticosterone response to restraint in rats

The present study sought to identify dishabituation of the hypothalamic-pituitary-adrenal (HPA) axis response to different psychological stressors. Young adult male Sprague Dawley rats were exposed to five, 1 h sessions of restraint stress on five consecutive days. On the sixth day, and 2 h before additional exposure to restraint, animals were subjected to 30 min of a small (27 cm square), elevated open field stressor (pedestal), which served as the dishabituating stimulus. We predicted HPA axis response dishabituation in chronically restrained rats exposed to the novel pedestal. Rats which underwent five days of restraint stress showed significantly blunted plasma corticosterone levels to restraint (habituation) as compared to restraint-naïve rats. However, rats which underwent five sessions of restraint responded with an enhanced habituation response when confronted with restraint shortly after exposure to the novel pedestal. Instead of HPA axis response dishabituation, we observed enhanced habituation. Subsequent experiments determined that a 1.25 mg/kg corticosterone injection could substitute for pedestal exposure to produce enhanced restraint habituation. Combined treatment with both the glucocorticoid receptor antagonist RU40555 (30 mg/kg) and the mineralocorticoid receptor antagonist RU28318 (50 mg/kg) blocked the expression of enhanced habituation after pedestal exposure. Thus, the delayed corticosterone negative feedback produced by novel stress led to enhanced expression of corticosterone response habituation.