Antidepressant-like effects of CP-154,526, a selective CRF1 receptor antagonist

Mansbach, Robert S.; Brooks, Elizabeth N; Chen, Yuhpyng L.

doi:10.1016/s0014-2999(97)00025-3

Cited by 181 publications

(90 citation statements)

References 29 publications

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“…Mansbach et al (1997) did find antalarmin to be active in a quite different model also labeled as learned helplessness, but using the very same procedures, D-Phe CRH (12-41) and antalarmin had contrasting effects. There are numerous potential explanations for this difference.…”

Section: Discussionmentioning

confidence: 90%

The Role of Corticotropin-Releasing Hormone in the Dorsal Raphe Nucleus in Mediating the Behavioral Consequences of Uncontrollable Stress

et al. 2002

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Inescapable shock (IS) produces subsequent interference with escape behavior and increased fear conditioning that has been linked to increased activity and release of serotonin (5-HT) from neurons within the caudal dorsal raphe nucleus (DRN) both at the time of IS and later behavioral testing. Extrahypothalamic corticotropin-releasing hormone (CRH) has been implicated in many stress-related phenomena and has recently been shown to increase DRN 5-HT activity in the same caudal DRN area at which IS increases 5-HT activity. The current set of studies therefore examined the role of CRH in mediating the behavioral sequelae of IS. Intra-DRN microinjection of the nonselective CRH receptor antagonist D-Phe CRH (12-41) blocked the ISinduced behavioral changes when administered before IS but not when administered before later behavioral testing. Furthermore, intra-DRN administration of CRH in the absence of IS dose-dependently mimicked the effects of IS and interfered with escape behavior and increased fear conditioning 24 hr later. This effect was specific to injection of CRH into the caudal DRN and was not produced by microinjection into the rostral DRN. Intracerebroventricular CRH produced escape deficits and potentiated fear conditioning 24 hr later at only much higher doses, further confirming the site specificity of the effects. The potential role of the caudal DRN in states of anxiety is discussed.Key words: corticotropin-releasing hormone; dorsal raphe nucleus; learned helplessness; serotonin; rats; shock Corticotropin-releasing hormone (CRH) plays a key role in integrating neural, endocrine, and behavioral responses to stressful stimuli (Dunn and Berridge, 1990;Owens and Nemeroff, 1993). Although endocrine consequences of stressors are mediated by CRH-secreting cells in the hypothalamus, behavioral and neurochemical sequelae of stressor exposure are regulated by extrahypothalamic CRH (Liang et al., 1992;Lee and Davis, 1997).Serotonin (5-HT) systems are also involved in mediating reactions to stressors, and CRH has been shown to interact with 5-HT systems (Kirby et al., 2000;Lowry et al., 2000). There are CRHimmunoreactive fibers associated with 5-HT neurons in the raphe nuclei (Cummings et al., 1983;Austin et al., 1997), as well as CRH receptor mRNA expression, immunoreactivity, and binding (Cummings et al., 1983;DeSouza, 1985;Chen et al., 2000). Although the effects of CRH on 5-HT neuronal firing have been reported to be primarily inhibitory in the rostral dorsal raphe nucleus (DRN; Kirby et al., 2000), Lowry et al. (2000) have recently identified a population of 5-HT neurons in the caudal DRN that are potently excited by CRH.Interestingly, the caudal region of the DRN has been implicated in the behavioral consequences of exposure to uncontrollable stressors that have been called "behavioral depression" (Weiss et al., 1981) or "learned helplessness" (Maier and Seligman, 1976). These terms refer to the general finding that stressors over which an organism has no behavioral control produce changes that do not occu...

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Section: Discussionmentioning

confidence: 90%

The Role of Corticotropin-Releasing Hormone in the Dorsal Raphe Nucleus in Mediating the Behavioral Consequences of Uncontrollable Stress

et al. 2002

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“…In mice the anxiolytic-like efficacy of CP-154,526 was judged superior to that of the atypical anxiolytic buspirone but was less robust in terms of the magnitude of the effects and the number of indices of anxiety affected than that of diazepam (Griebel et al 1998). Potential antidepressant-like effects of CP-154,526 have also been studied (Mansbach et al 1997), using the learned helplessness procedure, a putative model of depression with documented sensitivity to antidepressant drugs. These data support evidence implicating stress systems in the pathophysiology of depression and together with clinical evidence of pituitaryadrenocortical hyperactivation in affective disorders, provide a rationale for potential efficacy of small molecule CRF Type I receptor antagonists in the treatment of affective or anxiety-related disorders (Holsboer 1999).…”

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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“…The consistent preclinical results as well as clinical data indicating that CSF CRF levels are elevated in melancholic depression (Nemeroff et al 1984) have led to speculation that a non-peptide CRF antagonist might prove to have antidepressant and anxiolytic properties (Holsboer 1999;Gilligan et al 2000). Encouraging results from the first open label clinical trial (Zobel et al 2000) support the preclinical predictions (Mansbach et al 1997) that nonpeptide CRF antagonists may indeed prove useful in treating depression and anxiety.…”

mentioning

confidence: 88%

Effects of a Non-peptide CRF Antagonist (DMP696) on the Behavioral and Endocrine Sequelae of Maternal Separation

Maciag

Dent

Gilligan

et al. 2002

Neuropsychopharmacology

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Antidepressant-like effects of CP-154,526, a selective CRF1 receptor antagonist

Cited by 181 publications

References 29 publications

The Role of Corticotropin-Releasing Hormone in the Dorsal Raphe Nucleus in Mediating the Behavioral Consequences of Uncontrollable Stress

The Role of Corticotropin-Releasing Hormone in the Dorsal Raphe Nucleus in Mediating the Behavioral Consequences of Uncontrollable Stress

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

Effects of a Non-peptide CRF Antagonist (DMP696) on the Behavioral and Endocrine Sequelae of Maternal Separation

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