Antagonism of CRF2 receptors produces anxiolytic behavior in animal models of anxiety

Takahashi, Lorey K.; Ho, Sa V.; Livanov, Valentin; Graciani, Nilsa R.; Arnerić, Stephen P.

doi:10.1016/s0006-8993(01)02405-2

Cited by 130 publications

(91 citation statements)

References 49 publications

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“…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%

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%

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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“…Pharmacological studies on the role of CRF 2 receptors in anxiety-and stress-like responses have yielded equally conflicting results. For example, antagonism of CRF 2 receptors by icv administration of AS30 has been shown to reduce the facilitation of the acoustic startle reflex produced by central administration of CRF (Risbrough et al 2003) and produce anxiolyticlike effects in the elevated plus maze (Pelleymounter et al 2002;Takahashi et al 2001), whereas activation of CRF 2 receptors by icv infusions of the endogenous CRF 2 -preferring putative neuropeptide urocortin 2 produce anxiogenic-like effects (Pelleymounter et al 2002(Pelleymounter et al , 2004. On the other hand, this latter study showed that the anxiogenic-like effects of urocortin 2 were not attenuated by co-infusion of AS30, and also showed that icv administration CRF 2 -preferring ligand urocortin 3 had no effect on behavior in the elevated plus maze (Pelleymounter et al 2004), questioning the role of CRF 2 receptors in the behavioral actions of urocortin 2 and 3.…”

Section: Discussionmentioning

confidence: 99%

Anxiogenic and aversive effects of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis in the rat: role of CRF receptor subtypes

et al. 2006

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Rationale-Corticotropin releasing factor (CRF) produces anxiety-like and aversive effects when infused directly into the various regions of the brain, including the bed nucleus of the stria terminalis (BNST). However, the CRF receptor subtypes within the BNST mediating these phenomena have not been established.Objectives-We used selective CRF receptor antagonists to determine the receptor subtypes involved in the anxiogenic-like and aversive effects CRF in the BNST. Methods-MaleLong-Evans rats were bilaterally infused with CRF (0.2 or 1.0 nmol) either alone or in combination with the CRF 1 receptor antagonist CP154,526 or the CRF 2 receptor antagonist anti-sauvagine 30 (AS30) prior to behavioral testing in the elevated plus maze or place conditioning paradigms.Results-Intra-BNST administration of CRF produced a dose-dependent reduction in open arm entries and open arm time in the elevated plus maze, indicating an anxiogenic-like effect. These effects were inhibited by co-infusion of CP154,526 but not AS30, indicating that the anxiogeniclike effects of CRF in the BNST are mediated by CRF 1 receptors. Place conditioning with intra-BNST administration of CRF produced a dose-dependent aversion to the CRF-paired environment that was prevented by co-infusion of either CP154,526 or AS30, indicating that both CRF receptor subtypes mediate the aversive effects of this peptide. Intra-BNST infusions of the CRF receptor antagonists alone produced no effects in either behavioral paradigm.Conclusions-CRF 1 receptors in the BNST mediate the anxiogenic-like effects CRF in this region, whereas both CRF 1 and CRF 2 receptor subtypes mediate the conditioned aversive effects of this peptide within the BNST.

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“…At 45 min after treatment, adult Wistar rats were placed in a small cylindrical stainless-steel chamber (11 cm diameter Â 21 cm length) opened at one end, alongside one of the four walls of an open field (90 Â 90 cm 2 ) (Takahashi et al, 2001), and video recorded for 15 min in a dim light, sound-attenuated environment. Behavioral analyses were performed by blinded observers, using the Observer 3.0 software (Noldus, Wageningen, the Netherlands).…”

Section: Defensive Withdrawalmentioning

confidence: 99%

“…As an additional test of the anxiolytic-like properties of AM404, we evaluated the effects of this agent on defensive withdrawal in Wistar rats (Takahashi et al, 2001). AM404 (1-5 mg kg À1 , i.p.)…”

Section: Effects Of Am404 On Defensive Withdrawalmentioning

confidence: 99%

Anxiolytic-Like Properties of the Anandamide Transport Inhibitor AM404

Bortolato

Campolongo

Mangieri

et al. 2006

Neuropsychopharmacol

215

150

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The endocannabinoids anandamide and 2-arachidonoyglycerol (2-AG) may contribute to the regulation of mood and emotion. In this study, we investigated the impact of the endocannabinoid transport inhibitor AM404 on three rat models of anxiety: elevated plus maze, defensive withdrawal and separation-induced ultrasonic vocalizations. AM404 (1-5 mg kg À1 , intraperitoneal (i.p.)) exerted dosedependent anxiolytic-like effects in the three models. These behavioral effects were associated with increased levels of anandamide, but not 2-AG, in the prefrontal cortex and were prevented by the CB 1 cannabinoid antagonist rimonabant (SR141716A), suggesting that they were dependent on anandamide-mediated activation of CB 1 cannabinoid receptors. We also evaluated whether AM404 might influence motivation (in the conditioned place preference (CPP) test), sensory reactivity (acoustic startle reflex) and sensorimotor gating (prepulse inhibition (PPI) of the startle reflex). In the CPP test, AM404 (1.25-10 mg kg À1 , i.p.) elicited rewarding effects in rats housed under enriched conditions, but not in rats kept in standard cages. Moreover, AM404 did not alter reactivity to sensory stimuli or cause overt perceptual distortion, as suggested by its lack of effect on startle or PPI of startle. These results support a role of anandamide in the regulation of emotion and point to the anandamide transport system as a potential target for anxiolytic drugs.

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Antagonism of CRF2 receptors produces anxiolytic behavior in animal models of anxiety

Cited by 130 publications

References 49 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

Anxiogenic and aversive effects of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis in the rat: role of CRF receptor subtypes

Anxiolytic-Like Properties of the Anandamide Transport Inhibitor AM404

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