Corticotropin-releasing hormone receptors in the medial prefrontal cortex regulate hypothalamic–pituitary–adrenal activity and anxiety-related behavior regardless of prior stress experience

The hypothalamic–pituitary–adrenal (HPA) axis habituates, or gradually decreases its activity, with repeated exposure to the same stressor. During habituation, the HPA axis likely requires input from cortical and limbic regions involved in the processing of cognitive information that is important in coping to stress. Brain regions such as the medial prefrontal cortex (mPFC) are recognized as important in mediating these processes. The mPFC modulates stress-related behavior and some evidence suggests that the mPFC regulates acute and repeated stress-induced HPA responses. Interestingly, corticotropin-releasing hormone (CRH)-1 receptors, which integrate neuroendocrine, behavioral and autonomic responses to stress, are localized in the mPFC but have not been specifically examined with respect to HPA regulation. We hypothesized that CRH receptor activity in the mPFC contributes to stress-induced regulation of HPA activity and anxiety-related behavior and that CRH release in the mPFC may differentially regulate HPA responses in acutely compared to repeatedly stressed animals. In the present experiments, we found that blockade of CRH receptors in the mPFC with the non-selective receptor antagonist d-Phe-CRH (50 ng or 100 ng) significantly inhibited HPA responses compared to vehicle regardless of whether animals were exposed to a single, acute 30 min restraint or to the eighth 30 min restraint. We also found that intra-mPFC injections of CRH (20 ng) significantly increased anxiety-related behavior in the elevated plus maze in both acutely and repeatedly restrained groups compared to vehicle. Together, these results suggest an excitatory influence of CRH in the mPFC on stress-induced HPA activity and anxiety-related behavior regardless of prior stress experience.