Intracerebroventricular Administration of Corticotrophin‐Releasing Hormone Receptor Antagonists Produces Different Effects on Hypothalamic Pituitary Adrenal Responses to Novel Restraint Depending on the Stress History of the Animal

Corticotrophin‐releasing hormone (CRH) regulates acute stress‐induced changes in neuroendocrine function and behaviour. However, little is known about CRH functions in animals that have prior experience with repeated stress. Repeatedly‐stressed rats exhibit a habituated hypothalamic‐pituitary‐adrenal (HPA) response to a familiar, homotypic stressor but exhibit maintained or enhanced HPA responses to a novel, heterotypic stressor. We examined the effects of intracerebroventricular (i.c.v.) administration of two different nonselective CRH receptor antagonists, alpha‐helical CRH(9‐41) (ahCRH) or D‐Phe CRH(12‐41) (D‐PheCRH), on HPA responses to acute restraint in rats previously exposed to repeated cold stress (i.e. facilitated responses). Antagonists were administered as single i.c.v. injections prior to restraint to provide a general index of CRH function in control versus repeatedly‐stressed rats. CRH receptor blockade with either ahCRH or D‐PheCRH produced different effects on HPA responses to novel restraint depending on whether the animal had been previously cold stressed or not. Interestingly, some agonist‐type effects were observed but only in repeatedly‐stressed rats. In summary, these results indicate that manipulations of the CRH receptor have different effects on HPA activity depending on the stress history of the animal.