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

Oshima, Akihiro; Flachskamm, Cornelia; Reul, Johannes M. H. M.; Holsboer, Florian; Linthorst, Astrid C E

doi:10.1038/sj.npp.1300267

Cited by 61 publications

(34 citation statements)

References 72 publications

(115 reference statements)

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“…infusion of CRF, Ucn1 or Ucn2 14,22,48,69 is effective at increasing immediate-early gene expression within caudal regions of the DRN. In addition, several stress paradigms, CRF and its related peptides and the use of CRFR1 antagonists cause different changes in levels of 5-HT and 5-HIAA in the terminal regions, [70][71][72][73][74][75][76] underscoring the role of CRF and CRFrelated peptides in the regulation of extracellular 5-HT levels under basal and stress conditions.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…All experiments were performed on day 1 after the insertion of the microdialysis probe between 06:00 and 12:00 h to avoid interference with rodents' physiologically rising corticosterone levels in the afternoon (Oshima et al, 2003).…”

Section: In Vivo Microdialysis Proceduresmentioning

confidence: 99%

“…In contrast, in vivo microdialysis enables continuous sampling of glucocorticoids at their respective receptors within the brain, and only the free and biological active fraction of the hormone is determined. However, this approach has only been used scarcely for the assessment of HPA axis activity in mutant mice or in response to pharmacological manipulations (e.g., Sillaber et al, 1998;Linthorst et al, 2000;Oshima et al, 2003;Keeney et al, 2006).…”

Section: Article In Pressmentioning

confidence: 99%

The temporal dynamics of intrahippocampal corticosterone in response to stress-related stimuli with different emotional and physical load: An in vivo microdialysis study in C57BL/6 and DBA/2 inbred mice

Thoeringer

Sillaber²,

Roedel

et al. 2007

Psychoneuroendocrinology

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SummaryThere is strong evidence for a pivotal interaction of corticosteroid signalling and behavioral adaptation to stress. To further elucidate this relation, we monitored the dynamics of free corticosterone in the murine hippocampus of two inbred mouse strains using in vivo microdialysis. C57BL/6JOlaHsd (C57BL/6) and DBA/2OlaHsd (DBA/2) inbred mouse strains have been shown to differ in their anxiety-related and depression-like behavior and provide, thus, an interesting animal model to study the stimulus-response profile of the hypothalamus-pituitary-adrenocortical (HPA) system as a function of emotional and physical load. We, first, compared peripheral and intracerebral concentration patterns of corticosterone by simultaneous microdialysis of the jugular vein and the hippocampus in anesthetized mice and found strain differences in blood versus intracerebral free corticosterone concentrations. C57BL/6 showed almost the same steroid levels in either compartment, whereas DBA/2 mice displayed higher glucocorticoid levels in the circulation than in the hippocampus. This data suggest a strain difference in the tissue environment influencing the amount of biological active corticosterone at the receptor site. Measurements of intrahippocampal corticosterone in freely moving mice revealed that DBA/2 display a prolonged glucocorticoid increase in response to a single forced swimming stress (FST), as compared to C57BL/6 mice indicating a reduced inhibitory HPA axis feedback. Exposure to a novel environment (NE) induced a desensitization of the HPA system in DBA/2 animals as they show an attenuated intracerebral corticosterone dynamics after a subsequent FST. Testing animals in an elevated plus-maze (EPM), however, did not significantly stimulate coriticosterone release in either strain. The analysis of the area under the curve revealed a high amount of corticosterone released through FST and a low glucocorticoid release after NE or EPM exposure that are independent of the strain. This data indicate a strong stimulus dependency of corticosterone secretion that is strain independent, whereas the dynamics and feedback of the HPA axis is different between both inbred strains. Behavioral phenotyping of animals revealed a strong impact of microdialysis procedure on FST and EPM performance. Innate emotionality differences of both strains, however, were not affected. Though descriptive in nature, the present results suggest an altered corticosteroid signalling in the DBA/2 strain compared to C57BL/6 mice. Whether this observation causally underlies the differences in anxiety-related and depression-like behavior has to be further experimentally validated. In addition, our study highlights the use of in vivo microdialysis to assess the neuroendocrine endophenotype of animal models via profiling of stimulus-response patterns of stress hormones. ARTICLE IN PRESS

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“…Similarly, an acute intracerebroventricular administration of CRH in rats has been shown to result in a dose-dependent increase in the levels of hippocampal 5-HT and its metabolite, 5-hydroxyindoleacetic acid, suggesting the involvement of CRH-R1 [162]. Lastly, Oshima and colleagues [163] have reported alterations in hippocampal serotonergic neurotransmission in rats treated chronically with NBI 30775, a CRH-R1 antagonist, which has antidepressant action. A molecular mechanism by which CRH and 5-HT might interact has been proposed recently by Magalhaes and colleagues [164].…”

Section: E Hpa-axis and Monoaminergic Systemsmentioning

confidence: 98%

A unifying framework for depression: Bridging the major biological and psychosocial theories through stress

Roy¹,

Campbell²

2013

CIM

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A unifying framework for depression: Bridging the major biological and psychosocial theories through stress AbstractSeveral mechanisms for the development of depression have been proposed, and a comparative examination reveals considerable overlap. is paper begins by summarizing the conclusions drawn in the literature on the major biological theories: HPA-axis hyperactivity, the monoamine theory, the cytokine hypothesis/ macrophage theory, and structural changes to relevant brain regions and neurons. It then discusses the role of psychosocial stress as a bridge between the pathophysiology of depression and its predominantly psychosocial risk factors, touching upon theories o ered in psychology and in population health. is paper further proposes a unifying framework which integrates the major theories. e multiple systems involved, and the directional complexity among them, likely help to explain the wide-ranging symptoms associated with depression, and the wide variety of comorbid medical conditions. ey may also contribute to challenges in treatment, the diversity in symptoms and treatment outcomes among individuals, and the high rates of symptom persistence and relapse. e apparent bi-directionality of associations may suggest the existence of positive-feedback loops which aggravate symptoms; however, further bench research is required to con rm such phenomena. A better understanding of these interweaving associations is warranted. Additionally, given the signi cant in uence of socioeconomic and psychosocial factors on the aetiology of depression, population-level interventions that address the social determinants of health are required. Current individual-level pharmacologic approaches are designed to treat pathophysiology once it is underway, and current individual-level non-pharmacologic interventions (such as talk therapy) are designed to moderate the relationship between psychosocial stress and pathophysiology. In contrast, a key strategy for primary prevention lies in population-level interventions that address the predominantly social causes of one of depression's most notable risk factors: chronic psychosocial stress.

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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

Cited by 61 publications

References 72 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

The temporal dynamics of intrahippocampal corticosterone in response to stress-related stimuli with different emotional and physical load: An in vivo microdialysis study in C57BL/6 and DBA/2 inbred mice

A unifying framework for depression: Bridging the major biological and psychosocial theories through stress

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