Stress-induced behaviors require the corticotropin-releasing hormone (CRH) receptor, but not CRH

Abstract

Corticotropin-releasing hormone (CRH) is a central regulator of the hormonal stress response, causing stimulation of corticotropin and glucocorticoid secretion. CRH is also widely believed to mediate stress-induced behaviors, implying a broader, integrative role for the hormone in the psychological stress response. Mice lacking the CRH gene exhibit normal stress-induced behavior that is specifically blocked by a CRH type 1 receptor antagonist. The other known mammalian ligand for CRH receptors is urocortin. Normal and CRHdeficient mice have an identical distribution of urocortin mRNA, which is confined to the region of the Edinger-Westphal nucleus, and is absent from regions known to mediate stress-related behaviors. Since the Edinger-Westphal nucleus is not known to project to any brain regions believed to play a role in anxiety-like behavior, an entirely different pathway must be postulated for urocortin in the Edinger-Westphal nucleus to mediate these behaviors in CRH-deficient mice. Alternatively, an unidentified CRH-like molecule other than CRH or urocortin, acting through the CRH receptors in brain regions believed to mediate stressinduced behaviors, may mediate the behavioral response to stress, either alone or in concert with CRH.Stress, defined as the response of the body to any threatening demand (1), can be broadly separated into physiological responses, including the stimulation of adrenal glucocorticoid secretion, and behavioral responses, including anxiety and fearful behavior. Alterations in the stress-response system are believed to underlie many anxiety-related disorders (2-5). Corticotropinreleasing hormone (CRH) has been implicated in both physiological and behavioral stress responses. CRH was identified by its ability to stimulate adrenocorticotropic hormone (ACTH) secretion from anterior pituitary corticotrophs, thus activating the hypothalamic-pituitary-adrenal (HPA) axis (6). In addition, infusion of CRH into the brain was found to cause stress-like behaviors (7), suggesting that CRH integrates physiological and behavioral activities into a generalized stress response. Subsequently, many other pharmacological studies have implicated CRH in the behavioral response to stressors. These studies confirmed that intracerebral infusion of CRH induces stress-like behaviors and additionally that intracerebral infusions of CRH antagonists blunt the behavioral response to a stressor (8-10). Furthermore, transgenic mice that overexpress CRH exhibit increased anxiety-like behavior (11).The role of the CRH receptor in the behavioral stress response has been further evaluated. The two known CRH receptors, type 1 and type 2 (12), both consist of a 7-transmembrane helix functionally coupled to adenylate cyclase via G s . For the most part, the anatomical distributions of the two CRH receptors are distinct, with the type 1 receptor expressed in the central nervous system in regions including neo-, olfactory, and hippocampal cortices, subcortical limbic structures in the septal region and amygdala, ce...

The Corticosteroid Receptor Hypothesis of Depression

“…Mice with deletions of the CRH gene exhibit normal stress-induced behavior, confirming that CRH may not be the only physiologically active ligand of CRH receptors. If CRH is absent, other neuropeptides such as urocortin or other yet-to-be identified molecules acting at CRH1 or CRH2 receptors (and possibly CRH receptors yet-to-be discovered) can serve as anxiogenic or depressogenic signals (Weninger et al 1999). Studies by Liebsch et al (1995Liebsch et al ( , 1999, Heinrichs et al (1997), and Skutella et al (1998), who used antisense probes directed against the mRNA-encoding CRH-R1 and CRH-R2 in rats, and also studies involving mouse mutants lacking CRH-R1, suggested that CRH-R1 mediates anxiety-like behavior (Timpl et al 1998;Smith et al 1998) (Figure 2).…”

“…The behavioral role of urocortin still needs to be clarified. This neuropeptide binds with higher affinity to both CRH receptors and this may explain why anxiety-like responses to stressors in CRH null mutant mice are indistinguishable from wildtype mice (Weninger et al 1999). In the absence of CRH, urocortin may bind to CRH-R1 compensating the loss of CRH.…”

Anxiolytic Activity of the MGLU2/3 Receptor Agonist LY354740 on the Elevated Plus Maze is Associated with the Suppression of Stress-Induced c-Fos in the Hippocampus and Increases in c-Fos Induction in Several Other Stress-Sensitive Brain Regions

“…As mentioned above, LY354740 administration increased c-Fos expression in the EW (Figure 7i and 8), an oculomotor nucleus receiving projections from the pretectal nuclei. The EW has recently been implicated in the regulation of stress/anxiety via its urocortin-containing neurons (Vaughan et al, 1995;Kozicz et al, 1998;Weninger et al, 1999Weninger et al, , 2000Skelton et al, 2000;Kozicz, 2003), and was therefore grouped in the present study with the other stressrelated brain regions (Figure 7). …”

“…Besides oculomotor functions, recent reports suggest the involvement of the EW in stress responses, anxiolytic actions of chronic benzodiazepine administration, and alcohol consumption (Skelton et al, 2000;Weninger et al, 2000;Bachtell et al, 2003;Kozicz, 2003). The EW is the primary source of the novel corticotropin-related neuropeptide urocortin in the rat and mouse brain (Vaughan et al, 1995;Kozicz et al, 1998;Weninger et al, 1999). The functional role of urocortin pathway and activation of EW neurons is currently under intense investigation.…”

Intermale aggression in corticotropin-releasing factor receptor 1 deficient mice

“…Within the CNS and elsewhere, CRF acts primarily on CRFR1 [4,35,41], but can activate with less efficacy CRF receptor 2 (CRFR2) [22,39]. CRF related peptides, urocortin (Ucn) 1 and Ucn 3, can also elicit different aspects of fear and anxiety (behavioral manifestations of stress) by acting within specific brain regions [3,18,23].…”