Rationale-Central administration of corticotropin-releasing factor (CRF) elicits a specific pattern of behavioral responses resembling a stress-like state, and is anxiogenic in rodent models of anxiety.Objectives-Specific behaviors evoked by the administration of CRF were measured. The roles of CRF receptor subtypes and that of serotonergic and noradrenergic systems in mediating these responses were studied.Methods-Burying, grooming and head shakes were quantified in rats following intracerebroventricular administration of CRF and urocortin II and after pretreatment with antagonists. The role of forebrain norepinephrine in the behavioral responses to CRF (0.3 μg) was examined following pretreatment with the neurotoxin DSP-4 and that of serotonin after depletion using systemic administration of para-chlorophenylalanine (p-CPA).Results-CRF at 0.3 and 3.0 μg caused robust increases in burying, grooming and head shakes, but urocortin II was ineffective. Pretreatment with either antalarmin or propranolol significantly attenuated the CRF-evoked behaviors. Destruction of forebrain NE pathways blocked spontaneous burying behavior elicited by CRF and conditioned burying directed towards an electrified shock probe. In contrast, depletion of 5-HT selectively attenuated CRF-evoked grooming.Conclusions-Overt behavioral responses produced by CRF, burying, grooming, and head shakes, appeared to be mediated through the CRF 1 receptor. Spontaneous burying behavior evoked by CRF or conditioned burying directed towards a shock probe were disrupted by lesion of the dorsal noradrenergic bundle and may represent anxiety-like behavior caused by CRF activation of the LC. In contrast, CRF-evoked increases in grooming were dependent on serotonin.

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.