Corticotropin Releasing Hormone Type 2 Receptors in the Dorsal Raphe Nucleus Mediate the Behavioral Consequences of Uncontrollable Stress

Hammack, Sayamwong E.; Schmid, Megan J.; LoPresti, Matthew L.; Der-Avakian, Andre; Pellymounter, M.; Foster, Alan C.; Watkins, Linda R.; Maier, Steven F.

doi:10.1523/jneurosci.23-03-01019.2003

Cited by 162 publications

(143 citation statements)

References 57 publications

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“…administration caused an increase in c-Fos immunostaining in topographically organized subpopulations of serotonergic neurons in the DRN, specifically within the DRC and DRD. 22,48 Moreover, although injection of mouse Ucn2 to the DRC leads to increased 5-HT release in the BLA 23 and potentiation of conditioned fear, as well as escape deficits in a model of learned helplessness, 20 the injection of the CRFR2 antagonist, antisauvagine-30, and not of CRFR1 antagonists, showed anxiolytic effects, including reversal of the potentiation of conditioned fear and the escape deficits after exposure to inescapable stress. 20,93,94 Thus, these behaviors indicating heightened anxiety in response to uncontrollable stress seem to be mediated by CRFR2 receptors on serotonergic neurons in the DRC.…”

Section: Discussionmentioning

confidence: 97%

“…22,48 Moreover, although injection of mouse Ucn2 to the DRC leads to increased 5-HT release in the BLA 23 and potentiation of conditioned fear, as well as escape deficits in a model of learned helplessness, 20 the injection of the CRFR2 antagonist, antisauvagine-30, and not of CRFR1 antagonists, showed anxiolytic effects, including reversal of the potentiation of conditioned fear and the escape deficits after exposure to inescapable stress. 20,93,94 Thus, these behaviors indicating heightened anxiety in response to uncontrollable stress seem to be mediated by CRFR2 receptors on serotonergic neurons in the DRC. 24 Some overall conclusions that can be drawn from the present neurochemistry data set are that tissue concentrations of 5-HT and 5-HIAA are generally elevated in Ucn1/Ucn2 dKO mice within an anxiety-related neural circuit that receives projections from the caudal and dorsal parts of the DRN, regions of the DRN that are targeted by anxiety-related stimuli, anxiogenic drugs and anxiety-related neuropeptides, such as Ucn1 and Ucn2.…”

Section: Discussionmentioning

confidence: 97%

“…24 Some overall conclusions that can be drawn from the present neurochemistry data set are that tissue concentrations of 5-HT and 5-HIAA are generally elevated in Ucn1/Ucn2 dKO mice within an anxiety-related neural circuit that receives projections from the caudal and dorsal parts of the DRN, regions of the DRN that are targeted by anxiety-related stimuli, anxiogenic drugs and anxiety-related neuropeptides, such as Ucn1 and Ucn2. 20,22,48,67,82,90,95,96 These effects are largely driven by effects of genotype on both 5-HT and 5-HIAA tissue concentrations within females, with a smaller effect of genotype in males. Analyses of additional 5-HT projection regions will reveal how widespread the effect of genotype is on increased tissue concentrations of 5-HT and 5-HIAA.…”

Section: Discussionmentioning

confidence: 99%

“…This behavioral effect could be reversed by a CRFR2-, but not by a CRF receptor type 1 (CRFR1)-specific antagonist. 20 Activation of CRFR2 in the DRN was further shown to increase firing rates and c-Fos expression of 5-HT neurons, 21,22 as well as increase 5-HT release in stress-related brain nuclei such as the basolateral amygdaloid (BLA) nucleus. [23][24][25][26] Ucn1 is synthesized mainly by the midbrain Edinger-Westphal nucleus, and is involved in the regulation of behavioral responses to stress.…”

Section: Introductionmentioning

confidence: 99%

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Urocortin-1 and -2 double-deficient mice show robust anxiolytic phenotype and modified serotonergic activity in anxiety circuits

et al. 2009

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The urocortin (Ucn) family of neuropeptides is suggested to be involved in homeostatic coping mechanisms of the central stress response through the activation of corticotropin-releasing factor receptor type 2 (CRFR2). The neuropeptides, Ucn1 and Ucn2, serve as endogenous ligands for the CRFR2, which is highly expressed by the dorsal raphe serotonergic neurons and is suggested to be involved in regulating major component of the central stress response. Here, we describe genetically modified mice in which both Ucn1 and Ucn2 are developmentally deleted. The double knockout mice showed a robust anxiolytic phenotype and altered hypothalamic-pituitary-adrenal axis activity compared with wild-type mice. The significant reduction in anxiety-like behavior observed in these mice was further enhanced after exposure to acute stress, and was correlated with the levels of serotonin and 5-hydroxyindoleacetic acid measured in brain regions associated with anxiety circuits. Thus, we propose that the Ucn/ CRFR2 serotonergic system has an important role in regulating homeostatic equilibrium under challenge conditions.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Urocortin-1 and -2 double-deficient mice show robust anxiolytic phenotype and modified serotonergic activity in anxiety circuits

et al. 2009

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“…However, it is also possible that the observed effects were mediated by CRF 2 receptors and differential receptor availability of the peptides produced the apparent discrepancy. Indeed, several studies favor the involvement of CRF 2 receptors in regulating DRN functions, especially in the more caudal regions of the DRN (Hammack et al, 2003, Staub et al, 2006. Additionally, CRF binding protein (CRF-BP) has been reported to modulate the availability of CRF family peptides (Potter et al, 1992, Seasholtz et al, 2002.…”

mentioning

confidence: 99%

Chronic low dose ovine corticotropin releasing factor or urocortin II into the rostral dorsal raphe alters exploratory behavior and serotonergic gene expression in specific subregions of the dorsal raphe

et al. 2007

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Corticotropin releasing factor (CRF) family peptides play key roles in integrating neural responses to stress. Both major CRF receptors have been pharmacologically identified in the dorsal raphe nucleus (DRN), a stress sensitive and internally heterogeneous nucleus supplying many forebrain regions with serotonergic input. Despite the involvement of chronic stress and serotonergic dysfunction in human mood and anxiety disorders, little is known about the effects of chronic CRF receptor activation on the DRN. We infused ovine CRF (1ng/hr), urocortin II (UCNII, 1ng/hr), or vehicle alone into rat DRN over 6 days. During infusion, animals were allowed to freely explore an open field for 15 minutes on each of two days, with the addition of a novel object on the second day. Following behavioral testing, 5-HT 1A , 5-HT 1B , serotonin transporter (SERT), and tryptophan hydroxylase-2 (Tph2) expression were examined through the DRN by in situ hybridization. Ovine CRF infusion resulted in significantly decreased novel object touches, climbs, as well as increased latency to first novel object contact. UCNII had a similar but less dramatic effect, decreasing only climbing behavior. Both ovine CRF and UCNII blunted the decrease in corner time expected on reexposure to the open field. Both peptides also produced regionally specific changes in gene expression: 5-HT 1A expression was increased 30% in the mid-rostral ventromedial DRN, while SERT was decreased by 30% in the mid-caudal shell dorsomedial DRN. There also appeared to be a shift in the relative level of Tph2 expression between the ventromedial and core dorsomedial DRN at the mid-rostral level. Changes in 5-HT 1A , SERT, and relative Tph2 mRNA abundance were correlated with novel object exploration. These findings suggest chronic intra-DRN administration of CRF agonists decreases exploratory behavior, while producing subregionally limited changes in serotonergic gene expression. These studies may be relevant to mechanisms underlying behavioral changes after chronic stress. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptDepression and anxiety disorders are among the leading causes of morbidity, mortality, and disability in the United States (Greenberg et al., 2003). They are often comorbid, and both are highly associated with chronic exposure to stress. Multiple lines of evidence suggest that chronic and inescapable stress produce long lasting effects on brain function and behavior that play a prominent role in the development, maintenance, and recurrence of both depression and a variety of anxiety disorders (Gulley and Nemeroff, 1993, Arborelius et al., 1999, Ressler and Nemeroff, 2000.Altered serotonin neurotransmission appears to be a central mechanism inducing both depressive (Maes and Meltzer, 1995) and anxiety disorders (Ressler and Nemeroff, 2000). The majority of serotonergic fibers to forebrain regions thought to be involved in mood and anxiety regulation arise from the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN) ...

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Astressin‐amide and astressin‐acid are structurally different in dimethylsulfoxide

et al. 2007

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The C-terminally amidated CRF antagonist astressin binds to CRF-R1 or CRF-R2 receptors with low nanomolar affinity while the corresponding astressin-acid has >100 times less affinity. To understand the role of the amide group in binding, the conformations of astressin-amide and astressin-acid were studied in DMSO using NMR techniques. The 3D NMR structures show that the backbones of both analogs prefer an alpha-helical conformation, with a small kink around Gln(26). However, astressin-amide has a well-defined helical structure from Leu(27) to Ile(41) and a conformation very similar to the bioactive conformation reported by our group (Grace et al., Proc Natl Acad Sci USA 2007, 104, 4858-4863). In contrast, astressin-acid has an irregular helical conformation from Arg(35) onward, including a rearrangement of the side chains in that region. This structural difference highlights the crucial role of the C-terminal amidation for stabilization of astressin's bioactive conformation.

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Corticotropin Releasing Hormone Type 2 Receptors in the Dorsal Raphe Nucleus Mediate the Behavioral Consequences of Uncontrollable Stress

Cited by 162 publications

References 57 publications

Urocortin-1 and -2 double-deficient mice show robust anxiolytic phenotype and modified serotonergic activity in anxiety circuits

Urocortin-1 and -2 double-deficient mice show robust anxiolytic phenotype and modified serotonergic activity in anxiety circuits

Chronic low dose ovine corticotropin releasing factor or urocortin II into the rostral dorsal raphe alters exploratory behavior and serotonergic gene expression in specific subregions of the dorsal raphe

Astressin‐amide and astressin‐acid are structurally different in dimethylsulfoxide

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