Brain circuits involved in corticotropin-releasing factor-norepinephrine interactions during stress

Corticotropin-releasing factor (CRF)- and norepinephrine (NE)-containing neurons in the brain are activated during stress, and both have been implicated in the behavioral responses. NE neurons in the brain stem can stimulate CRF neurons in the hypothalamic paraventricular nucleus (PVN) to activate the hypothalamic-pituitary-adrenocortical axis and may affect other CRF neurons. CRF-containing neurons in the PVN, the amygdala, and other brain areas project to the area of the locus coeruleus (LC), and CRF injected into the LC alters the electrophysiologic activity of LC-NE neurons. Neurochemical studies have indicated that CRF applied intracerebroventricularly or locally activates the LC-NE system, and microdialysis and chronoamperometric measurements indicate increased NE release in LC-NE terminal fields. However, chronoamperometric studies indicated a significant delay in the increase in NE release, suggesting that the CRF input to LC-NE neurons is indirect. The reciprocal interactions between cerebral NE and CRF systems have been proposed to create a "feed-forward" loop. It has been postulated that a sensitization of such a feed-forward loop may underlie clinical depression. However, in the majority of studies, repeated or chronic stress has been shown to decrease the behavioral and the neurochemical responsivity to acute stressors. Repeated stress also seems to decrease the responsivity of LC neurons to CRF. These results do not provide support for a feed-forward hypothesis. However, a few studies using certain tasks have indicated sensitization, and some other studies have suggested that the effect of CRF may be dose dependent. Further investigations are necessary to establish the validity or otherwise of the feed-forward hypothesis.