Deciphering the Interaction of the Corticotropin-Releasing Factor and Serotonin Brain Systems in Anxiety-Related Disorders

Schema representing CRF-serotonin interactions in the dRN and their regulation by stress exposure. In the basal state (top diagram), dRN serotonergic neurons are tonically inhibited by GABAergic afferents, which limit the release of serotonin into dRN target brain regions. Exposure to an acute stressor (middle diagram) triggers the release of low levels of CRF into the dRN, which activate CRF₁ receptors and potentiate GABAergic transmission, thereby resulting in reduced serotonin levels in dRN limbic targets and active behavioral responses to stress. Exposure to stress also produces a redistribution of the CRF receptors expressed by the different neuronal populations of the dRN: CRF₁ receptors carried by nonserotonergic neurons internalize while CRF₂ receptors are recruited at the surface of serotonergic neurons and their level of expression increases (middle vs bottom diagrams). Repetition or intensification of the stressor triggers the release of higher levels of CRF into the dRN, which now activate CRF2 receptors and stimulate the activity of serotonergic neurons, thereby leading to a massive serotonin efflux in targeted limbic structures and passive stress-coping strategies (learned helplessness).