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.