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Florian Holsboer - One of the best experts on this subject based on the ideXlab platform.
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altered serotonergic neurotransmission but normal hypothalamic pituitary adrenocortical axis activity in mice chronically treated with the corticotropin releasing Hormone Receptor type 1 antagonist nbi 30775
Neuropsychopharmacology, 2003Co-Authors: Akihiko Oshima, Florian Holsboer, Cornelia Flachskamm, J M H M Reul, Astrid C E LinthorstAbstract:Antagonists of the Corticotropin-Releasing Hormone Receptor type 1 (CRH-R1) are regarded as promising tools for the treatment of stress-related psychiatric disorders. Owing to the intricate relationship between CRH and serotonin (5-HT), we studied the effects of chronic oral treatment of C57Bl6/N mice with the CRH-R1 antagonist NBI 30775 (formerly known as R121919) on hippocampal serotonergic neurotransmission during basal (on 15th day of treatment) and stress (forced swimming; on 16th day of treatment) conditions by in vivo microdialysis. Given the important role of CRH in the regulation of hypothalamic-pituitary-adrenocortical (HPA) axis activity and behavior, the effects of NBI 30775 on dialysate-free corticosterone levels, and on home cage and forced swimming-related behavior were also assessed. Chronic administration of NBI 30775 (18.4+/-0.9 mg/kg/day) did not result in alterations in food consumption and body weight. NBI 30775 caused complex changes in hippocampal serotonergic neurotransmission. Whereas no effects on the diurnal rhythms of 5-HT and its metabolite 5-hydroxyindoleacetic acid were found, the responses of the neurotransmitter and its metabolite to 10 min of forced swim stress were reduced and prolonged, respectively. NBI 30775 did not change free corticosterone levels over the diurnal rhythm. Moreover, NBI 30775-treated mice showed a similar forced swim stress-induced increase in corticosterone as observed in the control group. No effects of NBI 30775 on home cage, and swim stress-related active behaviors (climbing, swimming) and immobility were found. Thus, whereas chronic antagonism of CRH-R1 did not compromise HPA axis performance and behavior, distinct changes in serotonergic neurotransmission developed. Owing to the important role of 5-HT in the pathophysiology of mood and anxiety disorders, the latter observation may contribute to the therapeutical efficacy of CRH-R1 antagonists in these illnesses.
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Altered Serotonergic Neurotransmission but Normal Hypothalamic–Pituitary–Adrenocortical Axis Activity in Mice Chronically Treated with the Corticotropin-Releasing Hormone Receptor Type 1 Antagonist NBI 30775
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2003Co-Authors: Akihiko Oshima, Florian Holsboer, Cornelia Flachskamm, Johannes M. H. M. Reul, Astrid C E LinthorstAbstract:Antagonists of the Corticotropin-Releasing Hormone Receptor type 1 (CRH-R1) are regarded as promising tools for the treatment of stress-related psychiatric disorders. Owing to the intricate relationship between CRH and serotonin (5-HT), we studied the effects of chronic oral treatment of C57Bl6/N mice with the CRH-R1 antagonist NBI 30775 (formerly known as R121919) on hippocampal serotonergic neurotransmission during basal (on 15th day of treatment) and stress (forced swimming; on 16th day of treatment) conditions by in vivo microdialysis. Given the important role of CRH in the regulation of hypothalamic-pituitary-adrenocortical (HPA) axis activity and behavior, the effects of NBI 30775 on dialysate-free corticosterone levels, and on home cage and forced swimming-related behavior were also assessed. Chronic administration of NBI 30775 (18.4+/-0.9 mg/kg/day) did not result in alterations in food consumption and body weight. NBI 30775 caused complex changes in hippocampal serotonergic neurotransmission. Whereas no effects on the diurnal rhythms of 5-HT and its metabolite 5-hydroxyindoleacetic acid were found, the responses of the neurotransmitter and its metabolite to 10 min of forced swim stress were reduced and prolonged, respectively. NBI 30775 did not change free corticosterone levels over the diurnal rhythm. Moreover, NBI 30775-treated mice showed a similar forced swim stress-induced increase in corticosterone as observed in the control group. No effects of NBI 30775 on home cage, and swim stress-related active behaviors (climbing, swimming) and immobility were found. Thus, whereas chronic antagonism of CRH-R1 did not compromise HPA axis performance and behavior, distinct changes in serotonergic neurotransmission developed. Owing to the important role of 5-HT in the pathophysiology of mood and anxiety disorders, the latter observation may contribute to the therapeutical efficacy of CRH-R1 antagonists in these illnesses.
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Corticotropin-Releasing Hormone Receptor type 1-deficiency enhances hippocampal serotonergic neurotransmission: an in vivo microdialysis study in mutant mice
Neuroscience, 2002Co-Authors: R. G. Penalva, Florian Holsboer, Stephan Zimmermann, Wolfgang Wurst, Cornelia Flachskamm, Johannes M. H. M. Reul, Astrid C E LinthorstAbstract:Abstract Corticotropin-Releasing Hormone plays an important role in the coordination of various responses to stress. Previous research has implicated both Corticotropin-Releasing Hormone and the serotonergic system as causative factors in the development and course of stress-related psychiatric disorders such as major depression. To delineate the role of the Corticotropin-Releasing Hormone Receptor type 1 (CRH-R1) in the interactions between Corticotropin-Releasing Hormone and serotonergic neurotransmission, in vivo microdialysis was performed in CRH-R1-deficient mice under basal (home cage) and stress (forced swimming) conditions. Hippocampal dialysates were used to measure extracellular levels of serotonin and its metabolite 5-hydroxyindoleacetic acid, and free corticosterone levels to monitor the status of the hypothalamic–pituitary–adrenocortical axis. Moreover, behavioural activity was assessed by visual observation and a scoring paradigm. Both wild-type and heterozygous mutant mice showed a clear diurnal rhythm in free corticosterone. Free corticosterone concentrations were, however, lower in heterozygous mutant mice than in wild-type animals and undetectable in homozygous CRH-R1-deficient mice. Homozygous CRH-R1-deficient mice showed enhanced hippocampal levels of 5-hydroxyindoleacetic acid but not of serotonin during the light and the dark phase of the diurnal cycle, which may point to an enhanced synthesis of serotonin in the raphe-hippocampal system. Moreover, the mutation resulted in higher behavioural activity in the home cage during the light but not during the dark period. Forced swimming caused a rise in hippocampal serotonin followed by a further increase after the end of the stress paradigm in all genotypes. Homozygous and heterozygous mutant mice showed, however, a significantly amplified serotonin response to the forced swimming as compared to wild-type control animals. We conclude that CRH-R1-deficiency results in reduced hypothalamic–pituitary–adrenocortical axis activity, in enhanced synthesis of serotonin during basal conditions, and in an augmented response in extracellular levels of serotonin to stress. These data provide further evidence for the intricate relationship between Corticotropin-Releasing Hormone and serotonin and the important role of the CRH-R1 herein.
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expression of crhr1 and crhr2 in mouse pituitary and adrenal gland implications for hpa system regulation
Endocrinology, 2001Co-Authors: Marianne B Müller, Florian Holsboer, J Preil, Stephan Zimmermann, Adelheid E Kresse, U Renner, Günter K. Stalla, Martin E Keck, Wolfgang WurstAbstract:Deficiency of Corticotropin-Releasing Hormone Receptor I (CRHR1) reduces anxiety-related behavior in mice and severely impairs the stress response of the hypothalamic-pituitary-adrenocortical (HPA) system. Most recently, we could show that severe emotional stressors induce a significant rise in plasma ACTH even in mice deficient for the CRHR1 (Crhr1-1-) which is, however, not accompanied by an increase in plasma corticosterone concentration, suggesting that CRHR1 might be directly involved in the regulation of adrenal corticosterone release. We therefore used the Crhr1-1- mouse model to clarify the potential role of adrenal CRHR1 in the regulation of the HPA system and, in particular, of corticosterone secretion. In Crhr1-/- mice, intravenous ACTH administration failed to stimulate corticosterone secretion despite a significant upregulation of ACTH Receptor mRNA levels in the adrenal cortex of these mutants. Further, by means of RT-PCR and in situ hybridization analyses, we could provide first evidence th...
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stress hypercortisolism and corticosteroid Receptors in depression implications for therapy
Journal of Affective Disorders, 2001Co-Authors: Florian HolsboerAbstract:Clinical and preclinical studies have gathered substantial evidence that alterations of the stress Hormone system play a major, causal role in the development of depression. In this review article, a summary of studies sustaining that view is given and data are presented which demonstrate that depression is associated with an impairment of corticosteroid Receptor function that gives rise to an excessive release of neuroHormones to which a number of signs and symptoms characteristic of depression can be attributed. The studies referred to in the following unanimously support the concept of an antidepressant mechanism of action that exerts its effects beyond the cell membrane Receptors of biogenic amines and particularly includes the improvement of corticosteroid Receptor function. When activated by ligands, corticosteroid Receptors act as transcription factors in correspondence with numerous other transcription factors already known to be activated by antidepressants. Furthermore, the potential of drugs that interfere more directly with stress Hormone regulation, such as corticosteroid Receptor antagonists and Corticotropin-Releasing Hormone Receptor antagonists, is discussed.
Dimitris K. Grammatopoulos - One of the best experts on this subject based on the ideXlab platform.
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Association of glucocorticoid and type 1 Corticotropin-Releasing Hormone Receptors gene variants and risk for depression during pregnancy and post-partum.
Journal of psychiatric research, 2013Co-Authors: Lucy Darwin, Deole Nishigandh, Kandala Ngianga-bakwin, Steve Smith, Dimitris K. GrammatopoulosAbstract:Women with postnatal depression (PND) appear to have abnormal hypothalamic pituitary adrenal (HPA) axis responses to stress, which might involve a genetic variability component. We investigated association of genetic variants in the glucocorticoid Receptor (GR, NR3C1) and corticotropin releasing Hormone Receptor 1 (CRHR1) genes with increased risk for PND. Two hundred pregnant women were recruited prospectively and PND risk was assessed by the Edinburgh Postnatal Depression Scale (EPDS) during pregnancy and again 2-8 weeks post-natally (CW-GAPND study). The BclI and ER22/23EK single nucleotide polymorphisms (SNPs) of the GR and the haplotype-tagged rs1876828, rs242939 and rs242941 SNPs of the CRHR1 associated with genetic risk to depressive disorders were genotyped. A cut-off score of 10 was used to detect increased risk of PND. Association analysis was carried out in 140 patients that completed the study protocol. The BClI and rs242939 SNPs were over-represented in women with postnatal EPDS score >= 10 with significant allele association (p = 0.011 and
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Insights into mechanisms of corticotropin‐releasing Hormone Receptor signal transduction
British journal of pharmacology, 2012Co-Authors: Dimitris K. GrammatopoulosAbstract:During evolution, mammals have developed remarkably similar molecular mechanisms to respond to external challenges and maintain survival. Critical regulators of these mechanisms are the family of ‘stress’-peptides that consists of the Corticotropin-Releasing Hormone (CRH) and urocortins (Ucns). These neuropeptides ‘fine-tune’ integration of an intricate series of physiological responses involving the autonomic, endocrine, immune, cardiovascular and reproductive systems, which induce a spectrum of behavioural and homeostatic changes. CRH and Ucns exert their actions by activating two types of CRH Receptors (CRH-R), CRH-R1 and CRH-R2, which belong to the class-B1 family of GPCRs. The CRH-Rs exhibit signalling promiscuity facilitated by their ability to couple to multiple G-proteins and regulate diverse intracellular networks that involve intracellular effectors such as cAMP and an array of PKs in an agonist and tissue-specific manner, a property that allows them to exert unique roles in the integration of homeostatic mechanisms. We only now begin to unravel the plethora of CRH-R biological actions and the transcriptional and post-translational mechanisms such as alternative mRNA splicing or phosphorylation-mediated desensitization developed to tightly control CRH-Rs biological activity and regulate their physiological actions. This review summarizes the current understanding of CRH-R signalling complexity and regulatory mechanisms that underpin cellular responses to CRH and Ucns. LINKED ARTICLES This article is part of a themed section on Secretin Family (Class B) G Protein-Coupled Receptors. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue-1
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mapping structural determinants within third intracellular loop that direct signaling specificity of type 1 corticotropin releasing Hormone Receptor
Journal of Biological Chemistry, 2012Co-Authors: Anu Punn, Jing Chen, Maria Delidaki, Jiyou Tang, George Liapakis, Hendrik Lehnert, Michael A Levine, Dimitris K. GrammatopoulosAbstract:The type 1 Corticotropin-Releasing Hormone Receptor (CRH-R1) influences biological responses important for adaptation to stressful stimuli, through activation of multiple downstream effectors. The structural motifs within CRH-R1 that mediate G protein activation and signaling selectivity are unknown. The aim of this study was to gain insights about important structural determinants within the third intracellular loop (IC3) of the human CRH-R1α important for cAMP and ERK1/2 pathways activation and selectivity. We investigated the role of the juxtamembrane regions of IC3 by mutating amino acid cassettes or specific residues to alanine. Although simultaneous tandem alanine mutations of both juxtamembrane regions Arg292-Met295 and Lys311-Lys314 reduced ligand binding and impaired signaling, all other mutant Receptors retained high affinity binding, indistinguishable from wild-type Receptor. Agonist-activated Receptors with tandem mutations at the proximal or distal terminal segments enhanced activation of adenylyl cyclase by 50–75% and diminished activation of inositol trisphosphate and ERK1/2 by 60–80%. Single Ala mutations identified Arg292, Lys297, Arg310, Lys311, and Lys314 as important residues for the enhanced activation of adenylyl cyclase, partly due to reduced inhibition of adenylyl cyclase activity by pertussis toxin-sensitive G proteins. In contrast, mutation of Arg299 reduced Receptor signaling activity and cAMP response. Basic as well as aliphatic amino acids within both juxtamembrane regions were identified as important for ERK1/2 phosphorylation through activation of pertussis toxin-sensitive G proteins as well as Gq proteins. These data uncovered unexpected roles for key amino acids within the highly conserved hydrophobic N- and C-terminal microdomains of IC3 in the coordination of CRH-R1 signaling activity.
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Corticotropin-Releasing Hormone Receptor antagonists
European Journal of Endocrinology, 2006Co-Authors: E Zoumakis, Dimitris K. Grammatopoulos, G P ChrousosAbstract:Corticotropin-Releasing Hormone (CRH), CRH-related peptides, and CRH Receptors play major roles in coordinating the behavioral, endocrine, autonomic, and immune responses to stress. The wide influence of the CRH system on physiological processes in both brain and periphery implicates the respective peptides in the pathophysiology of numerous disorders characterized by dysregulated stress responses. The potential use of CRH antagonists is presently under intense investigation. Selective antagonists have been used experimentally to elucidate the role of CRH-related peptides in disease processes, such as anxiety and depression, sleep disorders, addictive behavior, inflammatory disorders, acute and chronic neurodegeneration, and preterm labor.
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The human myometrium expresses multiple isoforms of the Corticotropin-Releasing Hormone Receptor.
The Journal of clinical endocrinology and metabolism, 1995Co-Authors: Dimitris K. Grammatopoulos, S Thompson, E. W. HillhouseAbstract:Specific high affinity binding sites for CRH have been identified and characterized in the pituitary and central nervous system as well as in peripheral tissues. We recently identified and characterized a specific CRH Receptor in human myometrium that changes to a high affinity state before term. In view of this, we searched for Receptor heterogeneity in the pregnant and nonpregnant human myometrial CRH Receptor. Myometrial membranes were prepared by differential centrifugation from either pregnant (cesarian section) or nonpregnant (hysterectomy) myometrium. Using a specific RRA followed by isoelectric focusing and autoradiography, multiple isoforms of the human myometrial CRH Receptor were identified that were identical in both pregnant and nonpregnant myometrium. Five isoforms were identified (pI 4.65, 4.8, 4.95, 5.1, and 5.2). Reduction of disulfide bridges with reducing agents (dithiothreitol and cysteine) increased the specific binding of CRH to its myometrial Receptor, and the action of dithiothreit...
Kozo Hashimoto - One of the best experts on this subject based on the ideXlab platform.
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central type 2 corticotropin releasing Hormone Receptor mediates hypothalamic pituitary adrenocortical axis activation in the rat
Neuroendocrinology, 2007Co-Authors: Hiroshi Maruyama, Shinya Makino, Tohru Noguchi, Tatsuya Nishioka, Kozo HashimotoAbstract:In an attempt to clarify the role of the type 2 Corticotropin-Releasing Hormone (CRH) Receptor (CRHR-2) in the brain in activation of the hypothalamic-pituitary-adrenocortical axis, we conducted exper
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Down-regulation of Corticotropin-Releasing Hormone Receptor type 2β mRNA expression in the rat cardiovascular system following food deprivation
Regulatory peptides, 2002Co-Authors: Hossein Pournajafi Nazarloo, Koichi Asaba, Mitsuru Nishiyama, Yasushi Tanaka, Kozo HashimotoAbstract:Abstract The present study was conducted to assess the effect of nutritional stress induced by food deprivation on expression of messenger ribonucleic acid (mRNA) for Corticotropin-Releasing Hormone Receptor type 2β (CRH-R2β) in the rat cardiovascular system in the presence or absence of changes in circulating corticosterone. Food deprivation for 96 h caused a robust increase in plasma corticosterone levels and a significant decrease in CRH-R2β mRNA expression in the rat heart. Starvation for 48 and 96 h decreased CRH-R2β mRNA expression in the atria, ventricle as well as aorta of sham-adrenalectomized (sham) rats. Surprisingly, clamping plasma glucocorticoids at low levels by adrenalectomy with corticosterone pellet replacement (ADX+B) did not completely prevent starvation-induced decreases of CRH-R2β mRNA expression in the rat cardiovascular system. Urocortin (Ucn) mRNA expression was increased significantly by food deprivation in the heart of sham as well as ADX+B rats. We speculate that food deprivation may increase urocortin, which in turn down-regulates CRH-R2β mRNA expression in cardiovascular system. These data indicate that food deprivation despite the presence or absence of changes in circulating corticosterone may have an inhibitory effect on CRH-R2β mRNA expression in the rat cardiovascular system.
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Physiological Roles of Corticotropin-Releasing Hormone Receptor Type 2
Endocrine journal, 2001Co-Authors: Kozo Hashimoto, Shinya Makino, Koichi Asaba, Mitsuru NishiyamaAbstract:Recent investigations of the physiological roles of CRH-R2 are reviewed and summarized in Fig. 5. VMH CRH-R2 is more important than CRH-R1 in mediating anorexic effect of CRH or urocortin (UCN) and stress-induced reduction of food intake. CRH-R2 mediates a central anxiolytic response, opposing the anxiogenic effect of CRH mediated by CRH-R1. Hippocampal CRH-R1 mediates stress- induced enhancement of learning, while CRH-R2 in the lateral intermediate septum may act to impair learning. CRH-R1 mediates CRH-induced blood pressure elevation, while peripheral CRH-R2 mediates the hypotensive effect of systemically administered UCN and CRH. It is likely that CRH-R2 does not play an important role in hypothalamic-pituitary adrenal axis regulation, though it has been reported that CRH-R2-deficient mice showed hyper-response of ACTH and corticosterone. Peripheral CRH-R2 mediates UCN-induced mast cell degranulation, vascular permeability, and abdominal surgery -induced gastric stasis. These recent investigations have revealed that the existence of two CRH Receptors, which mediate some opposite effects, provides the CRH and UCN systems a high flexibility and dynamic role in the adaptation of the body to environmental challenge.
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Type 2 Corticotropin-Releasing Hormone Receptor mRNA expression in the heart in hypertensive rats
Life sciences, 1998Co-Authors: Shinya Makino, Koichi Asaba, Toshihiro Takao, Kozo HashimotoAbstract:Novel subtype of Corticotropin-Releasing Hormone Receptor (CRHR), designated type-2 CRHR (CRHR-2), mRNA was expressed not only in the central nervous system but also in the peripheral tissues such as the heart and skeletal muscle. The previous finding that type-1 CRHR mRNA is not detected in heart leads us to speculate that systemic administration of CRH induces hypotensive effects through CRHR-2, and that alterations in CRHR-2 in the heart may be implicated in blood pressure regulation. Therefore we examined CRHR-2 mRNA expression in the heart (at the level of ventricle) in spontaneously hypertensive rats (SHR) or DOCA-salt hypertensive rats (DOCA) using in situ hybridization histochemistry, compared to age-matched normotensive control rats. CRHR-2 mRNA levels in the heart were significantly higher in 7-week-old SHR than in 12-week-old SHR. Furthermore, CRHR-2 mRNA levels in SHR heart were significantly higher than those in normotensive controls, Wistar-Kyoto rats (WKY), at both 7 and 12 weeks of age. In contrast, CRHR-2 mRNA levels in DOCA heart were significantly lower than that of sham-operated controls after 6-weeks of treatment. Thus, alterations of CRHR-2 mRNA are dependent on the strain or experimental condition rather than as a consequence of hypertension. Plasma CRH levels in SHR or DOCA were not different from their normotensive control rats. CRH content in the ventricular heart of SHR or DOCA were also similar to normotensive controls. These results suggest that heart CRHR-2 mRNA levels are not influenced by circulating or locally existing CRH. Since alterations in heart CRHR-2 mRNA, as seen in SHR and DOCA, were bi-directional, the role of heart CRHR-2 in the regulation of hypertension remains to be elucidated.
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Differential regulation of type-1 and type-2α Corticotropin-Releasing Hormone Receptor mRNA in the hypothalamic paraventricular nucleus of the rat
Molecular Brain Research, 1997Co-Authors: Shinya Makino, Koichi Asaba, Toshihiro Takao, Mitsuru Nishiyama, T Takemura, Kozo HashimotoAbstract:Novel Corticotropin-Releasing Hormone Receptor (CRHR), designated type-2alpha CRHR (CRHR-2alpha), was recently cloned and functionally characterized. In situ hybridization study revealed that CRHR-2alpha mRNA had a distinct distribution from type-1 CRHR (CRHR-1) mRNA in the rat brain. Interestingly, CRHR-2alpha mRNA showed a relatively high expression in the hypothalamic paraventricular nucleus (PVN) even under unstressful condition. This may reflect the important role of CRHR-2alpha in the autoregulation of CRH secretion in the PVN. To determine the regulation of CRHR-2alpha mRNA expression in the PVN, we examined the alteration of CRHR-2alpha mRNA levels in the PVN in rats with lipopolysaccharide (LPS) injection, corticosterone (CORT) administration or adrenalectomy and compared with that of CRHR-1 mRNA, using in situ hybridization histochemistry. I.p. LPS injection (50 microg) induced a significant increase in PVN CRHR-1 mRNA at 3 and 6 h whereas CORT administration (10 mg/day for 12 days) or adrenalectomy (sacrificed 7 days after surgery) decreased CRHR-1 mRNA levels in the PVN. These alterations in PVN CRHR-1 mRNA are consistent with previous reports. In contrast, CRHR-2alpha mRNA levels in the PVN were not altered by any of these treatments. These results indicate that CRHR-1 and CRHR-2alpha mRNA are differentially regulated in the PVN. Further study will be necessary to elucidate the CRHR-2alpha function in the PVN.
Astrid C E Linthorst - One of the best experts on this subject based on the ideXlab platform.
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altered serotonergic neurotransmission but normal hypothalamic pituitary adrenocortical axis activity in mice chronically treated with the corticotropin releasing Hormone Receptor type 1 antagonist nbi 30775
Neuropsychopharmacology, 2003Co-Authors: Akihiko Oshima, Cornelia Flachskamm, J M H M Reul, F Holsboer, Astrid C E LinthorstAbstract:Altered Serotonergic Neurotransmission but Normal Hypothalamic–Pituitary–Adrenocortical Axis Activity in Mice Chronically Treated with the Corticotropin-Releasing Hormone Receptor Type 1 Antagonist NBI 30775
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altered serotonergic neurotransmission but normal hypothalamic pituitary adrenocortical axis activity in mice chronically treated with the corticotropin releasing Hormone Receptor type 1 antagonist nbi 30775
Neuropsychopharmacology, 2003Co-Authors: Akihiko Oshima, Florian Holsboer, Cornelia Flachskamm, J M H M Reul, Astrid C E LinthorstAbstract:Antagonists of the Corticotropin-Releasing Hormone Receptor type 1 (CRH-R1) are regarded as promising tools for the treatment of stress-related psychiatric disorders. Owing to the intricate relationship between CRH and serotonin (5-HT), we studied the effects of chronic oral treatment of C57Bl6/N mice with the CRH-R1 antagonist NBI 30775 (formerly known as R121919) on hippocampal serotonergic neurotransmission during basal (on 15th day of treatment) and stress (forced swimming; on 16th day of treatment) conditions by in vivo microdialysis. Given the important role of CRH in the regulation of hypothalamic-pituitary-adrenocortical (HPA) axis activity and behavior, the effects of NBI 30775 on dialysate-free corticosterone levels, and on home cage and forced swimming-related behavior were also assessed. Chronic administration of NBI 30775 (18.4+/-0.9 mg/kg/day) did not result in alterations in food consumption and body weight. NBI 30775 caused complex changes in hippocampal serotonergic neurotransmission. Whereas no effects on the diurnal rhythms of 5-HT and its metabolite 5-hydroxyindoleacetic acid were found, the responses of the neurotransmitter and its metabolite to 10 min of forced swim stress were reduced and prolonged, respectively. NBI 30775 did not change free corticosterone levels over the diurnal rhythm. Moreover, NBI 30775-treated mice showed a similar forced swim stress-induced increase in corticosterone as observed in the control group. No effects of NBI 30775 on home cage, and swim stress-related active behaviors (climbing, swimming) and immobility were found. Thus, whereas chronic antagonism of CRH-R1 did not compromise HPA axis performance and behavior, distinct changes in serotonergic neurotransmission developed. Owing to the important role of 5-HT in the pathophysiology of mood and anxiety disorders, the latter observation may contribute to the therapeutical efficacy of CRH-R1 antagonists in these illnesses.
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Altered Serotonergic Neurotransmission but Normal Hypothalamic–Pituitary–Adrenocortical Axis Activity in Mice Chronically Treated with the Corticotropin-Releasing Hormone Receptor Type 1 Antagonist NBI 30775
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2003Co-Authors: Akihiko Oshima, Florian Holsboer, Cornelia Flachskamm, Johannes M. H. M. Reul, Astrid C E LinthorstAbstract:Antagonists of the Corticotropin-Releasing Hormone Receptor type 1 (CRH-R1) are regarded as promising tools for the treatment of stress-related psychiatric disorders. Owing to the intricate relationship between CRH and serotonin (5-HT), we studied the effects of chronic oral treatment of C57Bl6/N mice with the CRH-R1 antagonist NBI 30775 (formerly known as R121919) on hippocampal serotonergic neurotransmission during basal (on 15th day of treatment) and stress (forced swimming; on 16th day of treatment) conditions by in vivo microdialysis. Given the important role of CRH in the regulation of hypothalamic-pituitary-adrenocortical (HPA) axis activity and behavior, the effects of NBI 30775 on dialysate-free corticosterone levels, and on home cage and forced swimming-related behavior were also assessed. Chronic administration of NBI 30775 (18.4+/-0.9 mg/kg/day) did not result in alterations in food consumption and body weight. NBI 30775 caused complex changes in hippocampal serotonergic neurotransmission. Whereas no effects on the diurnal rhythms of 5-HT and its metabolite 5-hydroxyindoleacetic acid were found, the responses of the neurotransmitter and its metabolite to 10 min of forced swim stress were reduced and prolonged, respectively. NBI 30775 did not change free corticosterone levels over the diurnal rhythm. Moreover, NBI 30775-treated mice showed a similar forced swim stress-induced increase in corticosterone as observed in the control group. No effects of NBI 30775 on home cage, and swim stress-related active behaviors (climbing, swimming) and immobility were found. Thus, whereas chronic antagonism of CRH-R1 did not compromise HPA axis performance and behavior, distinct changes in serotonergic neurotransmission developed. Owing to the important role of 5-HT in the pathophysiology of mood and anxiety disorders, the latter observation may contribute to the therapeutical efficacy of CRH-R1 antagonists in these illnesses.
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Corticotropin-Releasing Hormone Receptor type 1-deficiency enhances hippocampal serotonergic neurotransmission: an in vivo microdialysis study in mutant mice
Neuroscience, 2002Co-Authors: R. G. Penalva, Florian Holsboer, Stephan Zimmermann, Wolfgang Wurst, Cornelia Flachskamm, Johannes M. H. M. Reul, Astrid C E LinthorstAbstract:Abstract Corticotropin-Releasing Hormone plays an important role in the coordination of various responses to stress. Previous research has implicated both Corticotropin-Releasing Hormone and the serotonergic system as causative factors in the development and course of stress-related psychiatric disorders such as major depression. To delineate the role of the Corticotropin-Releasing Hormone Receptor type 1 (CRH-R1) in the interactions between Corticotropin-Releasing Hormone and serotonergic neurotransmission, in vivo microdialysis was performed in CRH-R1-deficient mice under basal (home cage) and stress (forced swimming) conditions. Hippocampal dialysates were used to measure extracellular levels of serotonin and its metabolite 5-hydroxyindoleacetic acid, and free corticosterone levels to monitor the status of the hypothalamic–pituitary–adrenocortical axis. Moreover, behavioural activity was assessed by visual observation and a scoring paradigm. Both wild-type and heterozygous mutant mice showed a clear diurnal rhythm in free corticosterone. Free corticosterone concentrations were, however, lower in heterozygous mutant mice than in wild-type animals and undetectable in homozygous CRH-R1-deficient mice. Homozygous CRH-R1-deficient mice showed enhanced hippocampal levels of 5-hydroxyindoleacetic acid but not of serotonin during the light and the dark phase of the diurnal cycle, which may point to an enhanced synthesis of serotonin in the raphe-hippocampal system. Moreover, the mutation resulted in higher behavioural activity in the home cage during the light but not during the dark period. Forced swimming caused a rise in hippocampal serotonin followed by a further increase after the end of the stress paradigm in all genotypes. Homozygous and heterozygous mutant mice showed, however, a significantly amplified serotonin response to the forced swimming as compared to wild-type control animals. We conclude that CRH-R1-deficiency results in reduced hypothalamic–pituitary–adrenocortical axis activity, in enhanced synthesis of serotonin during basal conditions, and in an augmented response in extracellular levels of serotonin to stress. These data provide further evidence for the intricate relationship between Corticotropin-Releasing Hormone and serotonin and the important role of the CRH-R1 herein.
Wolfgang Wurst - One of the best experts on this subject based on the ideXlab platform.
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regulation of the developing hypothalamic pituitary adrenal axis in corticotropin releasing Hormone Receptor 1 deficient mice
Neuroscience, 2003Co-Authors: Mathias V. Schmidt, Wolfgang Wurst, F Holsboer, Melly S Oitzl, Mario Muller, Seymour Levine, E R De KloetAbstract:Abstract During postnatal development, mice undergo a so-called stress hyporesponsive period, which is characterized by low basal corticosterone levels and the inability of mild stressors to induce a corticosterone response. The stress hyporesponsiveness is in part regulated by maternal factors. Twenty-four hours of deprivation results in an activation of basal and stress-induced corticosterone and a down-regulation of corticotropin releasing Hormone (CRH), mineralocorticoid Receptor (MR) and glucocorticoid Receptor (GR) expression in the brain. It has been hypothesized that the CRH Receptor 1 (CRHr1) may play an important regulatory role during development by mediating the effects of maternal deprivation. Using CRHr1-deficient mice we examined the role of this Receptor on the maternal deprivation effects and in regulating the expression of hypothalamic–pituitary–adrenal axis-related genes. We could demonstrate that the CRHr1 is essential for the activation of the corticosterone response following maternal deprivation, most likely due to the lack of the Receptor in the pituitary. Furthermore, we could show that the CRHr1 is regulating the expression of CRH and MRs. In contrast, effects of maternal deprivation during postnatal development on GRs are not mediated by this Receptor.
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Corticotropin-Releasing Hormone Receptor type 1-deficiency enhances hippocampal serotonergic neurotransmission: an in vivo microdialysis study in mutant mice
Neuroscience, 2002Co-Authors: R. G. Penalva, Florian Holsboer, Stephan Zimmermann, Wolfgang Wurst, Cornelia Flachskamm, Johannes M. H. M. Reul, Astrid C E LinthorstAbstract:Abstract Corticotropin-Releasing Hormone plays an important role in the coordination of various responses to stress. Previous research has implicated both Corticotropin-Releasing Hormone and the serotonergic system as causative factors in the development and course of stress-related psychiatric disorders such as major depression. To delineate the role of the Corticotropin-Releasing Hormone Receptor type 1 (CRH-R1) in the interactions between Corticotropin-Releasing Hormone and serotonergic neurotransmission, in vivo microdialysis was performed in CRH-R1-deficient mice under basal (home cage) and stress (forced swimming) conditions. Hippocampal dialysates were used to measure extracellular levels of serotonin and its metabolite 5-hydroxyindoleacetic acid, and free corticosterone levels to monitor the status of the hypothalamic–pituitary–adrenocortical axis. Moreover, behavioural activity was assessed by visual observation and a scoring paradigm. Both wild-type and heterozygous mutant mice showed a clear diurnal rhythm in free corticosterone. Free corticosterone concentrations were, however, lower in heterozygous mutant mice than in wild-type animals and undetectable in homozygous CRH-R1-deficient mice. Homozygous CRH-R1-deficient mice showed enhanced hippocampal levels of 5-hydroxyindoleacetic acid but not of serotonin during the light and the dark phase of the diurnal cycle, which may point to an enhanced synthesis of serotonin in the raphe-hippocampal system. Moreover, the mutation resulted in higher behavioural activity in the home cage during the light but not during the dark period. Forced swimming caused a rise in hippocampal serotonin followed by a further increase after the end of the stress paradigm in all genotypes. Homozygous and heterozygous mutant mice showed, however, a significantly amplified serotonin response to the forced swimming as compared to wild-type control animals. We conclude that CRH-R1-deficiency results in reduced hypothalamic–pituitary–adrenocortical axis activity, in enhanced synthesis of serotonin during basal conditions, and in an augmented response in extracellular levels of serotonin to stress. These data provide further evidence for the intricate relationship between Corticotropin-Releasing Hormone and serotonin and the important role of the CRH-R1 herein.
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expression of crhr1 and crhr2 in mouse pituitary and adrenal gland implications for hpa system regulation
Endocrinology, 2001Co-Authors: Marianne B Müller, Florian Holsboer, J Preil, Stephan Zimmermann, Adelheid E Kresse, U Renner, Günter K. Stalla, Martin E Keck, Wolfgang WurstAbstract:Deficiency of Corticotropin-Releasing Hormone Receptor I (CRHR1) reduces anxiety-related behavior in mice and severely impairs the stress response of the hypothalamic-pituitary-adrenocortical (HPA) system. Most recently, we could show that severe emotional stressors induce a significant rise in plasma ACTH even in mice deficient for the CRHR1 (Crhr1-1-) which is, however, not accompanied by an increase in plasma corticosterone concentration, suggesting that CRHR1 might be directly involved in the regulation of adrenal corticosterone release. We therefore used the Crhr1-1- mouse model to clarify the potential role of adrenal CRHR1 in the regulation of the HPA system and, in particular, of corticosterone secretion. In Crhr1-/- mice, intravenous ACTH administration failed to stimulate corticosterone secretion despite a significant upregulation of ACTH Receptor mRNA levels in the adrenal cortex of these mutants. Further, by means of RT-PCR and in situ hybridization analyses, we could provide first evidence th...
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impaired stress response and reduced anxiety in mice lacking a functional corticotropin releasing Hormone Receptor 1
Nature Genetics, 1998Co-Authors: Peter Timpl, Florian Holsboer, Adelheid E Kresse, Günter K. Stalla, J M H M Reul, Thomas Steckler, Inge Sillaber, Rainer Spanagel, Veronique Blanquet, Wolfgang WurstAbstract:Corticotropin-Releasing Hormone (CRH) is a potent mediator of endocrine, autonomic, behavioural and immune responses to stress, and has been implicated in the stress-like and other aversive consequences of drug abuse, such as withdrawal from alcohol1,2. Two CRH Receptors, Crhr1 and Crhr2, have been identified in the mouse3,4. Crhr1 is highly expressed in the anterior pituitary, neocortex, hippocampus, amygdala and cerebellum, and activation of this Receptor stimulates adenylate cyclase5,6. Here we show that in mice lacking Crhr1, the medulla of the adrenal gland is atrophied and stress-induced release of adrenocorticotropic Hormone (ACTH) and corticosterone is reduced. The homozygous mutants exhibit increased exploratory activity and reduced anxiety-related behaviour under both basal conditions and following alcohol withdrawal. Our results demonstrate a key role of the Crhr1 Receptor in mediating the stress response and anxiety-related behaviour.
