Corticotropin-releasing factor, norepinephrine, and stress

Corticotropin-releasing factor (CRF) and related peptides in the central nervous system appears to have activating properties on behavior and to enhance behavioral responses to stressors. CRF and urocortin injected into the brain produces increases in arousal as measured by locomotor activation and increased responsiveness to stressful stimuli. These effects of CRF appear to be independent of the pituitary adrenal axis and can be reversed by specific and selective CRF antagonists alpha-helical CRF9-41 and D-Phe CRF12-41. Perhaps more importantly, CRF antagonists can reverse behavioral responses to many stressors. These results suggest that endogenous CRF systems in the brain may have a role in mediating behavioral responses to stressors. Norepinephrine systems emanating from the nucleus locus coeruleus also long have been hypothesized to be involved in mediating behavioral constructs associated with alertness, arousal, and stress. Pharmacologic, physiologic, and neuroanatomic evidence supports an important role for a CRF-norepinephrine interaction in the region of the locus coeruleus in response to stressors that may be modality-specific where CRF neurons activate the locus coeruleus. One may hypothesize that another norepinephrine-CRF interaction may occur in the terminal projections of the forebrain norepinephrine systems in the paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminalis, and the central nucleus of the amygdala where norepinephrine stimulates CRF release. Such a feed-forward system may be particularly important in situations where an organism must mobilize not only the pituitary adrenal system but also the central nervous system, in response to environmental challenge. However, such a feed-forward mechanism in a fundamental brain-activating system may be particularly vulnerable to dysfunction and thus, may be the key to a variety of pathophysiologic conditions involving abnormal responses to stressors such as anorexia nervosa, anxiety, and affective disorders.