Glucocorticoid feedback increases the sensitivity of the limbic system to stress

In the hypothalamus, corticotropin-releasing hormone (CRH) has a well-described role initiating the hypothalamic-pituitary-adrenal (HPA) axis response to stress. Cortisol, released from the adrenal gland, exerts negative feedback on this axis. The role of extrahypothalamic CRH in stress responses is less well known. The purpose of this study was to measure the response of CRH in the amygdala to acute and repeated stress and to examine if cortisol had any effect on this response. Immunosensor-based microdialysis probes were used to measure CRH and cortisol in the amygdala and cortisol systemically in sheep exposed to a predator stress (a dog). Upon presentation of a dog, CRH increased in the amygdala of the sheep and then fell off. Cortisol levels rose both systemically and in the amygdala, and as they peaked, a second CRH response was observed. Repeated stress changed this response, with the magnitude of the first CRH peak decreasing while the second peak increased. Repeated stress also produced an exaggeration in both of the CRH peaks to presentation of a subsequent novel stress (a forelimb electric shock). Animals that had an escape route from the repeated dog stress did not show this exaggeration when faced subsequently with the novel stress. Administration of mifepristone, a glucocorticoid receptor antagonist, prior to the delivery of the repeat stress prevented subsequent changes in the CRH response. The data suggest that the amygdala shows a CRH response to presentation of a stressor acutely and repeatedly and that repeated stress can alter subsequent amygdala responsiveness to the same or a different stressor. This alteration appears dependent on circulatory glucocorticoids.