A non peptidic corticotropin releasing factor receptor antagonist attenuates fever and exhibits anxiolytic-like activity

Lundkvist, Johan; Chai, Zhifang; Teheranian, Roya; Hasanvan, Homa; Bartfai, Tamás; Jenck, F.; Widmer, Ulrich; Moreau, Jean‐Luc

doi:10.1016/0014-2999(96)00337-8

Cited by 135 publications

(55 citation statements)

References 16 publications

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“…Treatment with CRFR1-selective antagonists results in decreased anxiety-like effects in rodents (Lundkvist et al, 1996;Griebel et al, 1998;Radulovic et al, 1999) and monkeys (Habib et al, 2000). In direct contrast, increased levels of anxiety-like behavior were detected in mice deficient for CRFR2 (Bale et al, 2000;Kishimoto et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Mice Deficient for Both Corticotropin-Releasing Factor Receptor 1 (CRFR1) and CRFR2 Have an Impaired Stress Response and Display Sexually Dichotomous Anxiety-Like Behavior

et al. 2002

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Corticotropin-releasing factor (CRF) and its family of peptides are critical coordinators of homeostasis whose actions are mediated through their receptors, CRF receptor 1 (CRFR1) and CRFR2, found throughout the CNS and periphery. The phenotypes of mice deficient in either CRFR1 or CRFR2 demonstrate the critical role these receptors play. CRFR1-mutant mice have an impaired stress response and display decreased anxiety-like behavior, whereas CRFR2-mutant mice are hypersensitive to stress and display increased anxiety-like behavior. To further elucidate the roles of both CRF receptors and determine their interaction in behaviors, we have generated mice deficient in both CRFR1 and CRFR2. The behavioral phenotype of these mice demonstrates a novel role of the mother's genotype on development of pup anxiety. We have found that although the female double-mutant mice display anxiolytic-like behavior, the male double-mutant mice show significantly more anxiety-like behavior compared with the females. We have also determined that the dam's CRFR2 genotype affects the anxiety-like behavior of the male mice, such that a pup born to a heterozygous or mutant dam displays significantly more anxiety-like behavior regardless of that pup's genotype. Double-mutant mice also display an even greater impairment of their hypothalamic-pituitary-adrenal axis response to stress than that of the CRFR1-mutant mice. CRF mRNA levels are elevated in CRFR1-and double-mutant mice, and urocortin III and vasopressin mRNA levels are increased in CRFR2-and double-mutant mice. These results indicate that both CRFR1 and CRFR2 have critical roles in gene regulation and the maintenance of homeostasis in response to stress.

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Section: Discussionmentioning

confidence: 99%

Mice Deficient for Both Corticotropin-Releasing Factor Receptor 1 (CRFR1) and CRFR2 Have an Impaired Stress Response and Display Sexually Dichotomous Anxiety-Like Behavior

et al. 2002

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“…In particular, the nonpeptidic CRF 1 antagonist CP-154,526 is reported to exert anxiolytic-like activity in the elevated Plus Maze test in rats (Lundkvist et al 1996) to blunt physical signs of morphine withdrawal (Iredale et al 2000) and to attenuate fear-potentiated startle (Schulz et al 1996). A nonpeptide CRF 1 receptor antagonist, CRA1000, is reported to attenuate stress-induced shortening of pentobarbital hypnosis (Arai et al 1998) and to reverse the anxiogenic-like effect of a swim stressor on Data reflect the latency in seconds from insertion of the rat into the cage prior to initiation of burying of the electrified shock probe and total duration of probe burying in the Defensive Burying Test.…”

Section: Discussionmentioning

confidence: 99%

Brain Penetrance, Receptor Occupancy and Antistress In Vivo Efficacy of a Small Molecule Corticotropin Releasing Factor Type I Receptor Selective Antagonist

Heinrichs

Souza

Schulteis

et al. 2002

Neuropsychopharmacology

143

112

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The widely distributed brain corticotropin-releasing factor Type 1 (CRF 1 ) receptor has been strongly implicated in the increased emotionality accompanying exposure to environmental stressors (Steckler and Holsboer 1999). First, exogenous administration of a mixed CRF receptor agonist such as CRF or urocortin in testing models of anxiety produces anxiogenic-like behavior and potentiates the effects of stressor exposure (Koob and Heinrichs 1999;Moreau et al. 1997). Second, limbic and brain stem regions thought to subserve arousal and fear-like behaviors are enriched with CRF 1 receptors (Chalmers et al.

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“…In analogy, the novel, non-peptidergic CRF 1 antagonists, NBI27914, CRA1000, CRF1001 (all anilinopyrimidines), and CP154,526 (a pyrrollopyrimidine), inhibited the anxiogenic actions of CRF (Guanowsky et al 1997;Smagin et al 1998;Okuyama et al 1999). However, like several studies of peptidergic antagonists in rats under non-stressed conditions (Heinrichs et al 1992;Menzaghi et al 1994;Spina et al 2000), with the exception of NBI27914, they all failed to elicit anxiolytic activity alone in a plus-maze procedure (Lundkvist et al 1996;Griebel et al 1998;Okuyama et al 1999). Further, whereas Griebel et al (1998) reported modest anxiolytic actions of CP154,526 in a light-dark box paradigm in mice, in other studies, CP154,526, CRA1000, and CRA1001 were ineffective in this model unless mice were pre-exposed to stress (Guanowsky et al 1997;Okuyama et al 1999).…”

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confidence: 91%

Anxiolytic Properties of the Selective, Non-peptidergic CRF1 Antagonists, CP154,526 and DMP695 A Comparison to Other Classes of Anxiolytic Agent

Millan

2001

Neuropsychopharmacology

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The selective, non-peptidergic corticotropin-releasing factor (CRF) 1 receptor antagonists, CP154,526 and DMP695, dose-dependently increased punished responses of rats in a Vogel conflict test and enhanced social interaction (SI) of rats in an unfamiliarCorticotropin-releasing factor (CRF) plays a crucial role in modulation of the release of adrenocorticotrophic hormone from the anterior pituitary (De Souza 1995). In addition, CRF is broadly distributed throughout the mammalian central nervous system (CNS), being concentrated in corticolimbic regions such as amygdala, hippocampus, and periaqueductal gray (PAG) and frontal cortex (FCX), as well as the locus coeruleus (LC) and dorsal raphe nucleus (DRN), the origin of ascending adrenergic and serotonergic projections, respectively (Sawchenko et al. 1993;Van Bockstaele et al. 1996;Price et al. 1998;Steckler and Holsboer 1999). In line with this organization, independently of the hypothalamocorticotrophic axis, cerebral CRF-containing neurones fulfill an important role in the control of emotional behavior (Adamec and McKay 1993;De Souza 1995;Mitchell 1998;Steckler and Holsboer 1999;Smagin and Dunn 2000), actions expressed via two principal subtypes of CRF receptor, both of which positively couple to adenyl cyclase (Grigoriadis et al. 1996). CRF 1 receptors bind CRF and a related neuropeptide, urocortin, with high affinity whereas CRF 2 receptors display a NO . 4 distinct preference for the latter (Donaldson et al. 1996;Grigoriadis et al. 1996). Of several splice variants of the latter, the CRF 2 ␣ subtype is found predominantly in the rodent CNS, notably in several corticolimbic regions enriched in CRF itself, such as the hippocampus, medial amygdala, septum, olfactory bulb, and raphe nuclei, although species differences in this regard should be pointed out (Chalmers et al. 1995;Sánchez et al. 1999). Studies of mRNA encoding CRF 1 receptors and of the corresponding peptide have established a contrasting pattern of distribution in rats with a predominance of CRF 1 over CRF 2 ␣ sites in anterior pituitary, FCX and basolateral amygdala, as well as high levels in the hippocampus and PAG (Potter et al. 1994;Chalmers et al. 1995;Sánchez et al. 1999;Chen et al. 2000).These observations provide a neuroanatomical substrate for a potential role of CRF 1 and/or CRF 2 receptors in the control of mood (Coplan et al. 1996;Steckler and Holsboer 1999), and, in this regard, there is a diversity of evidence implicating CRF 1 sites in the modulation of anxious states. First, several studies have reported anxiogenic actions of CRF (and urocortin) upon i.c.v. administration (see Steckler and Holsboer, 1999) and similar effects have been seen upon direct introduction into the dorsal PAG (Martins et al. 1997), basolateral amygdala (Sajdyk et al. 1999), and hippocampus (Radulovic et al. 1999), structures possessing a high density of CRF 1 receptors. Second, direct evidence for participation of CRF 1 receptors in anxiogenic actions is derived from studies of antisense probes for their ...

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A non peptidic corticotropin releasing factor receptor antagonist attenuates fever and exhibits anxiolytic-like activity

Cited by 135 publications

References 16 publications

Mice Deficient for Both Corticotropin-Releasing Factor Receptor 1 (CRFR1) and CRFR2 Have an Impaired Stress Response and Display Sexually Dichotomous Anxiety-Like Behavior

Mice Deficient for Both Corticotropin-Releasing Factor Receptor 1 (CRFR1) and CRFR2 Have an Impaired Stress Response and Display Sexually Dichotomous Anxiety-Like Behavior

Brain Penetrance, Receptor Occupancy and Antistress In Vivo Efficacy of a Small Molecule Corticotropin Releasing Factor Type I Receptor Selective Antagonist

Anxiolytic Properties of the Selective, Non-peptidergic CRF1 Antagonists, CP154,526 and DMP695 A Comparison to Other Classes of Anxiolytic Agent

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