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

Maciag, Carla; Dent, Gersham; Gilligan, Paul J.; He, Li; Dowling, Krista; Ko, Tracey; Levine, Seymour; Smith, Mark A.

doi:10.1016/s0893-133x(01)00398-0

Cited by 52 publications

(27 citation statements)

References 31 publications

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“…Then the signals were processed by a PC equipped with a LabVIEW program, especially designed for sleep EEG analysis (National Instruments, SEA Kö ln, Germany). Polygraphic data were all stored on a computer and processed offline later with the LabVIEW-based acquisition program, in which a Fast Fourier Transform (FFT) algorithm served for power spectrum analysis of particular EEG frequency contents, that is, d (0.5-5 Hz), y (6-9 Hz), a (10-15 Hz) and b (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Using the aid of the FFT algorithm, adapted from a report by Louis et al, 16 the spectral analysis was also undertaken to serve semiautomatic classification of the particular vigilance state as awake, non-REM sleep or REM sleep that were defined in 4-s epochs.…”

Section: Sleep Recordings and Data Processingmentioning

confidence: 99%

“…The dose and the timing of administration were chosen according to an earlier report, in which DMP696 blocks stressinduced ACTH secretion. 17 The same animals received vehicle only (0.25% methylcellulose in sterile water) as a control group on the other day at the same timing during SD. Drug volumes were 5 ml kg -1 .…”

Section: Sleep Recordings and Data Processingmentioning

confidence: 99%

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Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep

et al. 2009

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Impaired sleep and enhanced stress hormone secretion are the hallmarks of stress-related disorders, including major depression. The central neuropeptide, corticotropin-releasing hormone (CRH), is a key hormone that regulates humoral and behavioral adaptation to stress. Its prolonged hypersecretion is believed to play a key role in the development and course of depressive symptoms, and is associated with sleep impairment. To investigate the specific effects of central CRH overexpression on sleep, we used conditional mouse mutants that overexpress CRH in the entire central nervous system (CRH-COE-Nes) or only in the forebrain, including limbic structures (CRH-COE-Cam). Compared with wild-type or control mice during baseline, both homozygous CRH-COE-Nes and -Cam mice showed constantly increased rapid eye movement (REM) sleep, whereas slightly suppressed non-REM sleep was detected only in CRH-COE-Nes mice during the light period. In response to 6-h sleep deprivation, elevated levels of REM sleep also became evident in heterozygous CRH-COE-Nes and -Cam mice during recovery, which was reversed by treatment with a CRH receptor type 1 (CRHR1) antagonist in heterozygous and homozygous CRH-COE-Nes mice. The peripheral stress hormone levels were not elevated at baseline, and even after sleep deprivation they were indistinguishable across genotypes. As the stress axis was not altered, sleep changes, in particular enhanced REM sleep, occurring in these models are most likely induced by the forebrain CRH through the activation of CRHR1. CRH hypersecretion in the forebrain seems to drive REM sleep, supporting the notion that enhanced REM sleep may serve as biomarker for clinical conditions associated with enhanced CRH secretion.

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Section: Sleep Recordings and Data Processingmentioning

confidence: 99%

Section: Sleep Recordings and Data Processingmentioning

confidence: 99%

Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep

et al. 2009

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“…In a perinatal context, administration of exogenous CRF disrupts several indices of nurturant interaction such as maternal behaviors in the dam, vocalizations of isolated pups, and milk letdown (Pedersen et al, 1991;Almeida et al, 1994). In contrast, the CRF 1 receptor antagonist DMP 696 (4-[1,3-dimethoxyprop-2-ylamine]-2,7-dimethyl-8-[2,4-dichlorophenyl]-pyrazolo[1,5-a]-1,3,5-triazine) is reported to facilitate social interaction in rats (Maciag et al, 2002). Moreover, dramatic species differences in CRF receptor distribution in monogamous versus nonmonogamous meadow voles suggests a role for CRF in facilitation of pair bonding (Lim et al, 2003).…”

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confidence: 99%

Corticotropin-Releasing Factor in Brain: A Role in Activation, Arousal, and Affect Regulation

Heinrichs

Koob²

2004

J Pharmacol Exp Ther

324

223

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Organisms exposed to challenging stimuli that alter the status quo inside or outside of the body are required for survival purposes to generate appropriate coping responses that counteract departures from homeostasis. Identification of an executive control mechanism within the brain capable of coordinating the multitude of endocrine, physiological, and functional coping responses has high utility for understanding the response of the organism to stressor exposure under normal or pathological conditions. The corticotropin-releasing factor (CRF)/urocortin family of neuropeptides and receptors constitutes an affective regulatory system due to the integral role it plays in controlling neural substrates of arousal, emotionality, and aversive processes. In particular, available evidence from pharmacological intervention in multiple species and phenotyping of mutant mice shows that CRF/urocortin systems mediate motor and psychic activation, stimulus avoidance, and threat recognition responses to aversive stimulus exposure. It is suggested that affective regulation is exerted by CRF/urocortin systems within the brain based upon the sensitivity of local brain sites to CRF/urocortin ligand administration and the appearance of hypothalamo-pituitary-adrenocortical activation following stressor exposure. Moreover, these same stress neuropeptides may constitute a mechanism for learning to avoid noxious stimuli by facilitating the formation of so-called emotional memories. A conceptual framework is provided for extrapolation of animal model findings to humans and for viewing CRF/urocortin activation as a continuum measure linking normal and pathological states.Many experimental studies performed in animals support the role of corticotropin-releasing factor (CRF) peptides and receptors as mediators of interoceptive coping reactions to environmental or physiological challenges; however, the advent of small molecule ligands for CRF receptors suitable for administration in human beings raises the question of what insights, if any, anti-stress pharmacology exerted via CRF manipulations in animals provides for human biology and psychopathology. The present review addresses how the evidence for the adaptive utility of CRF systems provides a basis for predicting the consequences of brain CRF system activation or deactivation in man. The thesis most strongly supported by the available experimental evidence is that: 1) activating, 2) avoidant, and 3) learning/memory functions of CRF systems have evolved to serve affective regulatory needs in man and animals. The term affective can be defined as "relating to, arising from, or influencing feelings or emotions" (Webster's Ninth Collegiate Dictionary) whereas the related phrase affective disorder describes a disturbance of mood where mood is defined as a prolonged emotion that colors the whole psychic life (American Psychiatric Association, 1994). The reader familiar with the term homeostasis may be interested in one testable postulate that a certain environmental stimulus intensity...

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“…In a rat defensive withdrawal test of anxiety, acute oral administration of DMP696 (3 mg/kg) reduces the latency for a rat to exit from an isolated box and reverses the stressinduced increases in plasma corticosterone levels without any effect on locomotor activity or motor coordination McElroy et al, 2002). In addition, at a higher concentration (30 mg/kg), DMP696 attenuates the enhanced stress response caused by maternal separation in rats (Maciag et al, 2002).…”

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confidence: 99%

Receptor Occupancy of Nonpeptide Corticotropin-Releasing Factor 1 Antagonist DMP696: Correlation with Drug Exposure and Anxiolytic Efficacy

Li¹,

Hill²,

Wong³

et al. 2003

J Pharmacol Exp Ther

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4-(1,3-Dimethoxyprop-2-ylamine)-2,7-dimethyl-8-(2,4-dichlorophenyl)-pyrazolo[1,5-a]-1,3,5-triazine (DMP696) is a highly selective and potent, nonpeptide corticotropin-releasing factor 1 (CRF 1 ) antagonist. In this study, we measured in vivo CRF 1 receptor occupancy of DMP696 by using ex vivo ligand binding and quantitative autoradiography and explored the relationship of receptor occupancy with plasma and brain exposure and behavioral efficacy. In vitro affinity (IC 50 ) of DMP696 to brain CRF 1 receptors measured using the brain section binding autoradiography in this study is similar to that assessed using homogenized cell membrane assays previously. The ex vivo binding assay was validated by demonstrating that potential underestimation of receptor occupancy with this procedure could be minimized by identifying an appropriate in vitro incubation time (40 min) based upon the dissociation kinetics of DMP696. Orally administrated DMP696 dose dependently occupied CRF 1 receptors in the brain, with ϳ60% occupancy at 3 mg/kg. In the defensive withdrawal test of anxiety, this dose of DMP696 produced approximately 50% reduction in the exit latency. The time course of plasma and brain drug levels paralleled that of receptor occupancy, with peak exposure at 90 min after dosing. The plasma-free concentration of DMP696 corresponding to 50% CRF 1 receptor occupancy (in vivo IC 50 , 1.22 nM) was similar to the in vitro IC 50 (ϳ1.0 nM). Brain concentrations of DMP696 were over 150-fold higher than the plasma-free levels. In conclusion, doses of DMP696 occupying over 50% brain CRF 1 receptors are consistent with doses producing anxiolytic efficacy in the defense withdrawal test of anxiety, and the IC 50 value estimated in vivo based on plasmafree drug concentrations is consistent with the in vitro IC 50 value.Corticotropin releasing factor (CRF), a 41-amino acid peptide, plays a pivotal role in the behavioral, endocrine, immune, and autonomic responses of the body to stress (Owens and Nemeroff, 1991). In addition to the hypothalamic paraventricular nucleus where it was originally identified, CRF is also widely distributed across brain regions (Chalmers et al., 1996;Heinrichs and De Souza, 1999;Gilligan et al., 2000a). The physiological functions of CRF are mediated by at least two G-protein coupled receptors, CRF 1 and CRF 2 (including splice variants CRF 2␣ , CRF 2␤ , CRF 2␥ ), both of which are linked to adenylyl cyclase activation but have distinct brain distributions. CRF 1 receptors are widespread in the cortex, limbic system, cerebellum, and pituitary, whereas CRF 2 receptors are dominant in subcortical areas including the lateral septum (CRF 2␣ ), ventromedial hypothalamus (CRF 2␣ ), and choroid plexus (CRF 2␤ ) (De Souza, 1987;Chalmers et al., 1995;Primus et al., 1997;Rominger et al., 1998).Increasing evidence suggests that the CRF system is involved in pathophysiology of anxiety disorders (Heinrichs and De Souza, 1999;Gilligan et al., 2000a). Intracerebroventricular administration of CRF induces stress beha...

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

Abstract: We examined whether blockade of corticotropin-releasing factor (CRF)

Cited by 52 publications

References 31 publications

Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep

Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep

Corticotropin-Releasing Factor in Brain: A Role in Activation, Arousal, and Affect Regulation

Receptor Occupancy of Nonpeptide Corticotropin-Releasing Factor 1 Antagonist DMP696: Correlation with Drug Exposure and Anxiolytic Efficacy

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