Is Corticotropin‐Releasing Factor a Mediator of Stress Responses? a

Corticotropin-releasing factor (CRF) was isolated and characterized by Vale et a f . I as a 41-amino acid peptide. It is generally believed to be the major active principle that elicits the secretion of adrenocorticotropin hormone (ACTH) from the pituitary.'.' CRF is synthesized in neurons of the paraventricular nucleus (PVN) of the hypothalamus. These neurons project to the median eminence region, where terminals secrete CRF directly into the blood. Transported in the portal blood vessels to the anterior pituitary, CRF stimulates the release of ACTH into the general circulation, which subsequently elicits the secretion of glucocorticoids from the adrenal cortex. This cascade constitutes activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is considered to be characteristic, and perhaps diagnostic, of In addition to the localization of CRF within the PVN, CRF-like immunoreactivity has been identified in many extrahypothalamic regions of the brain. 73 A similar distribution is found for bioactive CRF.9 The highest concentrations of extrahypothalamic immunoreactive CRF are found in neocortex, areas of the limbic system, and regions involved in the regulation of the autonomic nervous system. High-affinity binding sites for CRF have been observed with a similar regional distribution, using both quantitative autoradiographic and biochemical techniques. A neurotransmitter function for CRF is suggested because CRF-like immunoreactivity is reported to be released from samples of fresh brain tissue by K t in a Cazc-dependent manner.12 Moreover, responses to iontophoretic application of CRF vary with the region; inhibition of cell firing has been recorded in the thalamus and lateral septum, whereas excitation occurred in the cortex and hypothalamus." Thus cerebral CRF may have a neurotransmitter function in brain, in addition to its ability to activate the HPA axis. The release of extrahypothalamic CRF may be related to stressful situations, because regionally specific changes in the cerebral concentrations of CRF occur following both acute and chronic stressful treatments. l4 Moreover, in one brief report there was an increase in the cerebrospinal fluid (CSF) concentration of CRF in stressed rats. l5 There are many reports of neurochemical, physiological, endocrine, and behavioral responses following administration of CRF to animals. Many of these responses resemble those observed during stress. These findings prompted the suggestion that CRF may coordinate a whole body response in tress.'^." In support of this hypothesis, a number of reports indicate that CRF-antagonists can attenuate or reverse stress-induced changes in physiological, behavioral, and endocrine function. This paper will review these findings,