Dexamethasone nonsuppression in transgenic mice expressing antisense RNA to the glucocorticoid receptor

Stec, I.; Barden, Nicholas; Reul, Johannes M. H. M.; Holsboer, Florian

doi:10.1016/0022-3956(94)90031-0

Cited by 68 publications

(41 citation statements)

References 17 publications

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“…This resulted in a mouse expressing GR antisense mainly in neuronal tissue and this mutant was expected to be a well-suited animal model of depression associated with impaired GR function (Pepin et al 1992). This transgenic mouse was extensively studied and the main findings that emerged were the following: 1) these mice needed higher dexamethasone dosages than control mice in order to display corticosterone suppression under basal conditions or following CRH (Stec et al 1994); 2) CRH-elicited ACTH was higher in transgenic mice but corticosterone was lower in comparison to controls ; 3) these mice showed decreased corticosterone response to exogenous ACTH ); 4) when stressed, these mice showed increased ACTH levels, whereas corticosterone levels remain unchanged (Karanth et al 1997); 5) Dijkstra et al (1998) showed reduced activity of CRH neurons in the PVN of these mice and decreased sensitivity of pituitary CRH-R1 mRNA to stimulus-induced desensitisation; 6) these mice displayed an enhanced locomotorstimulating effect to morphine, a response that is reflected by an enhanced dopaminergic activity within the mesolimbic system (Spanagel et al 1996); 7) in these mice, responses to endotoxin were aberrant as noted by Linthorst and coworkers (1999), confirming that immune function is critically determined by appropriate GR function; 8) several studies (e.g., Montkowski et al 1995;Rousse et al 1997;Rochford et al 1997; showed that these mice have impairments in learning and memory paradigms which are also influenced by age; 9) Steckler et al (1999) concluded that allocentric spatial navigation is impaired whereas egocentric navigation is unimpaired. The latter authors suggested that the observed effects were due to hippocampal dysfunction secondary to GR deficiency and possible compensatory changes.…”

Section: Transgenic Mice Expressing Gr Antisensementioning

confidence: 99%

The Corticosteroid Receptor Hypothesis of Depression

Holsboer

2000

Neuropsychopharmacology

1,982

1,228

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Clinical EvidenceUntil now, the serendipitous discovery of antidepressants in the 1950s has profoundly inspired hypotheses of the pathogenesis of depression. The well-known pharmacological effects of antidepressants on presynaptic uptake transporters and degradating enzymes (i.e., MAO) of serotonin and norepinephrine has focused research on causality and treatment of depression on the metabolism of functional biogenic amines and the capacity of their respective receptors to alter intracellular signaling pathways that ultimately induce changes in gene activity. Elevated circulating levels of stress hormones among depressives were recognized even before antidepressants were discovered, but these changes were seen as epiphenomena, reflecting the stressful experience of depression, although M. Bleuler (1919) already demonstrated that hormones have diverse psychotropic effects and suggested hormone treatments as potential antidepressants. A vast amount of evidence has accumulated, that reject the view that altered stress hormone secretions in depression are epiphenomenal. During the past decade, several research groups formulated a hypothesis relating aberrant stress hormone dysregulation to causality of depression and submitted that antidepressants may act through normalisation of these HPA changes (

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Section: Transgenic Mice Expressing Gr Antisensementioning

confidence: 99%

The Corticosteroid Receptor Hypothesis of Depression

Holsboer

2000

Neuropsychopharmacology

1,982

1,228

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“…Mice with decreased glucocorticoid receptor gene expression (by transgenic expression of antisense mRNA directed against the receptor) exhibit reduced hypothalamic CRH expression [20], enhanced stress-associated ACTH response [21][22][23], and impaired efficiency of glucocorticoid-mediated negative feedback [21,[23][24][25]. These mice exhibit deficits in spatial learning, enhanced responses to novelty and decreased locomotion in familiar environments [6].…”

Section: Modulation By Mineralocorticoid and Glucocorticoid Receptorsmentioning

confidence: 99%

Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways

Taylor

Fricker

Devi

et al. 2005

Cellular Signalling

142

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Antidepressants are commonly used in the treatment of anxiety and depression, medical conditions that affect ~17-20% of the population. The clinical effects of antidepressants take several weeks to manifest, suggesting that these drugs induce adaptive changes in brain structures affected by anxiety and depression. In order to develop shorter-acting and more effective drugs for the treatment of anxiety and depression, it is important to understand how antidepressants bring about their beneficial effects. Recent reports suggest that antidepressants can induce neurogenesis in the adult brain, although the mechanisms involved are not clearly understood. In this review, we describe the different neurotransmitter systems that are affected by anxiety and depression and how they are modulated by antidepressant treatment with a focus on signaling molecules and pathways that are activated during neurotransmitter receptor induced neurogenesis.

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“…GR-i mice showed reduced GR mRNA levels (ϳϪ50 to Ϫ70%) predominantly in brain (Pepin et al, 1992) and reduced HPA axis response to glucocorticoids (Stec et al, 1994;Barden, 1999). As a result of GR-i function, HPA axis regulation is highly disturbed, and these animals have been proposed to be a transgenic model for depression (Holsboer and Barden, 1996).…”

Section: Introductionmentioning

confidence: 99%

Neurochemical and Behavioral Alterations in Glucocorticoid Receptor-Impaired Transgenic Mice after Chronic Mild Stress

Froger¹,

Palazzo²,

Boni³

et al. 2004

J. Neurosci.

105

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Mice (GR-i) bearing a transgene encoding a glucocorticoid receptor (GR)antisense RNA under the control of a neuron-specific neurofilament promoter were used to investigate the effects of a 4 week chronic mild stress (CMS) on the hypothalamo-pituitary-adrenocortical (HPA) axis and the serotoninergic system in a transgenic model of vulnerability to affective disorders. GR-i mice showed a decrease in both GR-specific binding (hippocampus and cerebral cortex) and GR mRNA levels [hippocampus, cerebral cortex, and dorsal raphe nucleus (DRN)] as well as a deficit in HPA axis feedback control (dexamethasone test) compared with paired wild-type (WT) mice. In the latter animals, CMS exposure caused a significant decrease in both GR mRNA levels and the density of cytosolic GR binding sites in the hippocampus, whereas, in the DRN, GR mRNA levels tended to increase. In contrast, in stressed GR-i mice, both GR mRNA levels and the density of GR binding sites were significantly increased in the hippocampus, cerebral cortex, and DRN. Electrophysiological recordings in brainstem slices and [␥-35 S]GTP-S binding measurements to assess 5-HT 1A receptor functioning showed that CMS exposure produced a desensitization of DRN 5-HT 1A autoreceptors in WT, but not in GR-i, mice. In addition, CMS was found to facilitate choice behavior of WT, but not GR-i, mice in a decision-making task derived from an alternation paradigm. These results demonstrate that impaired GR functioning affects normal adaptive responses of the HPA axis and 5-HT system to CMS and alters stress-related consequences on decision-making behaviors.

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Dexamethasone nonsuppression in transgenic mice expressing antisense RNA to the glucocorticoid receptor

Cited by 68 publications

References 17 publications

The Corticosteroid Receptor Hypothesis of Depression

The Corticosteroid Receptor Hypothesis of Depression

Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways

Neurochemical and Behavioral Alterations in Glucocorticoid Receptor-Impaired Transgenic Mice after Chronic Mild Stress

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