Increased CRF₂ expression in the dorsal raphe is associated with passive behavioral responses to stress

Abstract

The dorsal raphe (DR)‐serotonin (5‐HT) system is implicated in stress‐related psychiatric disorders, like depression. Corticotropin‐releasing factor (CRF) modulates activity of this system during stress via activation of two receptors: CRF1 and CRF2. CRF1 mediated inhibition of the DR‐5‐HT system facilitates active behavioral responses to stress. In contrast, CRF2 can excite the DR‐5‐HT system, an effect that may mediate passive responses to stress. Here we used genetic, behavioral, and pharmacological models to determine whether changes in CRF2 expression in the DR are associated with passive behavior. Western Blots were first used to demonstrate that rats of the behaviorally passive Wistar Kyoto strain express more CRF2 protein in the DR than Sprague‐Dawley (SD) rats. In the second experiment, SD rats exposed to chronic social defeat, which results in passive behavior on the forced swim test (FST), expressed more CRF2 in the DR than their unstressed counterparts. Finally, chronic antidepressant treatment that decreases passive responses on the FST resulted in fewer CRF2 in the DR. None of these models altered DR expression of CRF1. These studies suggest that greater CRF2 expression in the DR correlates with a passive behavioral strategy. Because passive responses to stress are associated with increased vulnerability to depression in humans, CRF2 may be a novel target for treating stress‐related disorders.