Corticotropin-Releasing Factor From Rodents to Primates: Translational Hope Expresses Itself, Pun Intended

Corticotropin-releasing factor (CRF) is a neuropeptide in the brain and body that coordinates hormonal, sympathetic, and behavioral responses to stressors. Since its discovery in 1981 ( ), literally thousands of articles have been published that support its role in these three functional domains. CRF controls corticotropin secretion and in turn glucocorticoid activation in the face of acute stressor exposure via its actions as a releasing factor in the paraventricular nucleus of the hypothalamus. Vale and colleagues first demonstrated that CRF initiates the hypothalamic-pituitary-adrenal (HPA) axis neuroendocrine stress response by binding CRF₁ receptors on anterior pituitary corticotropes to release adrenocorticotropic hormone ( ). CRF controls sympathetic activation via its actions as a neurotransmitter in the brainstem ( ), and CRF via CRF₁ receptors controls behavioral responses to stressors, from activation to freezing, anxiety-like responses, and fear conditioning via its actions as a neurotransmitter in the extended amygdala [for review, see Zorrilla et al. ( )]. CRF and CRF₁ receptors are widely distributed in stress-responsive brain regions, including the neocortex, central extended amygdala, medial septum, hippocampus, thalamus, cerebellum, and autonomic midbrain and hindbrain nuclei ( ). CRF in the gastrointestinal system plays a key role in modulating gastrointestinal motility and as such may play a key role in stress-related physiological disorders, such as irritable bowel syndrome ( ). In human psychiatric disorders, CRF has been implicated in anxiety and depressive disorders and addiction, again largely based on preclinical animal models ( ) and correlational measures of CRF in cerebrospinal fluid and postmortem brains ( ). Much of the preclinical work that implicates endogenous CRF in biological function has relied on both peptide and small-molecule antagonists. In rodents, CRF antagonists have profound effects in blocking physiological and behavioral responses to stressors ( , ).