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Stephen G. Matthews - One of the best experts on this subject based on the ideXlab platform.
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the effect of long term insulin treatment with and without antecedent hypoglycemia on neuropeptide and Corticosteroid Receptor expression in the brains of diabetic rats
Brain Research Bulletin, 2008Co-Authors: Karen Inouye, Stephen G. Matthews, Owen Chan, Jessica T Y Yue, Marcus H Andrews, Mladen VranicAbstract:We previously demonstrated that while diabetic animals receiving long-term insulin treatment exhibited some impairment in their corticosterone response to hypoglycemia, the stress response to hypoglycemia was completely absent when these animals were subjected to recurrent hypoglycemia. In the current study, we examined potential mechanisms that may contribute to defects in the adrenocortical response to hypoglycemia in long-term insulin-treated diabetic animals exposed to antecedent hypoglycemia. Whereas insulin-treated diabetic animals exhibited a significant rise in corticotrophin-releasing hormone (CRH) mRNA levels during hypoglycemia, exposure to antecedent hypoglycemia completely abolished this response. Moreover, expression of hippocampal mineralocorticoid Receptors (MR) mRNA, which normally act to suppress hypothalamo-pituitary-adrenal activity, decreased in the normal control and insulin-treated diabetic groups in response to hypoglycemia, whereas MR mRNA levels remained at baseline in animals subjected to antecedent hypoglycemia. Interestingly, hippocampal glucocorticoid Receptor (GR) mRNA levels decreased in all three treatment groups following the hypoglycemic clamp. While GR mRNA levels in the paraventricular nucleus were lower in normal controls following hypoglycemia, this trend just failed to reach statistical significance in the two diabetic groups. These data suggest that (1) recurrent hypoglycemia, much like uncontrolled diabetes, has a pronounced effect on hippocampal mineralocorticoid Receptor mRNA expression that may prevent it, and presumably also the stress axis, from responding properly to a subsequent bout of hypoglycemia, and (2) while long-term insulin treatment was sufficient to restore some of these responses in diabetic animals, tighter glycemic control may be necessary to see full restoration of the stress response.
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prenatal glucocorticoid exposure alters hypothalamic pituitary adrenal function and blood pressure in mature male guinea pigs
The Journal of Physiology, 2004Co-Authors: S Banjanin, Amita Kapoor, Stephen G. MatthewsAbstract:Pregnant guinea pigs were treated with dexamethasone (1 mg kg−1) or vehicle on days 40–41, 50–51 and 60–61 of gestation, after which animals delivered normally. Adult male offspring were catheterized at 145 days of age and subjected to tests of hypothalamic–pituitary–adrenal (HPA) axis function in basal and activated states. Animals exposed to dexamethasone in utero (mat-dex) exhibited increased hippocampus-to-brain weight ratio, increased adrenal-to-body weight ratio and increased mean arterial pressure. There were no effects on gestation length, birth weight and postnatal growth. There were no overall differences in diurnal plasma adrenocorticotropic hormone (ACTH) and cortisol profiles, though there were subtle differences during the subjective afternoon between control and mat-dex offspring. A significant decrease in initial ACTH suppression was observed following dexamethasone injection in mat-dex offspring compared to control offspring. Molecular analysis revealed significantly increased MR mRNA expression in the limbic system and particularly in the dentate gyrus in mat-dex offspring. In the anterior pituitary, both pro-opiomelanocortin (POMC) and glucocorticoid Receptor (GR) mRNA levels were significantly elevated in mat-dex offspring. In conclusion, (1) repeated prenatal treatment with synthetic glucocorticoid (sGC) permanently programmes organ growth, blood pressure and HPA regulation in mature male offspring and these changes involve modification of Corticosteroid Receptor expression in the brain and pituitary; (2) the effects of prenatal sGC exposure on HPA function appear to change as a function of age, indicating the importance of investigating HPA and cardiovascular outcome at multiple time points throughout life.
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repeated antenatal glucocorticoid treatment decreases hypothalamic corticotropin releasing hormone mrna but not Corticosteroid Receptor mrna expression in the fetal guinea pig brain
Journal of Neuroendocrinology, 2001Co-Authors: L Mccabe, D Marash, Antai Li, Stephen G. MatthewsAbstract:: Approximately 10% of pregnant women are treated with synthetic glucocorticoids in late gestation, to promote fetal lung maturation. The effectiveness of this treatment has led to the use of repeated dose regimens, with little knowledge of the impact on neuroendocrine development. Animal studies have recently shown that repeated fetal glucocorticoid exposure can lead to permanent changes in hypothalamic-pituitary-adrenal (HPA) function in offspring. In this study, we hypothesized that such treatment modifies corticotropin releasing hormone (CRH), glucocorticoid Receptor (GR) and mineralocorticoid Receptor (MR) systems in the developing limbic system and hypothalamus. Pregnant guinea-pigs were treated with dexamethasone, betamethasone or vehicle on days 40,41,50,51,60 and 61 of gestation (birth = 68 days). On day 62, guinea-pigs were killed and the fetuses rapidly removed. Glucocorticoid treatment resulted in a dose-dependent reduction in plasma cortisol concentrations in both male and female fetuses. There was also a significant reduction in CRH mRNA expression in the hypothalamic paraventricular nucleus. In contrast, exposure to glucocorticoid increased MR mRNA expression in the hippocampus (CA1/2 and CA3) and dentate gyrus of female fetuses. There was a small but significant increase in GR mRNA expression in limbic structures in male fetuses following treatment with 1 mg/kg dexamethasone. However, there was no significant effect of glucocorticoid exposure on hippocampal GR mRNA expression in female fetuses, or hypothalamic GR mRNA in either males or females. In conclusion, repeated maternal glucocorticoid treatment inhibits fetal HPA function. The fact that CRH mRNA levels were reduced indicates that synthetic glucocorticoids enter the fetal brain. By contrast, fetal glucocorticoid exposure does not downregulate GR mRNA, and increases MR mRNA expression. The latter likely reflects removal of circulating endogenous ligand (cortisol). These alterations may form the basis for permanently modified HPA activity in later life.
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maternal nutrient restriction 48 h modifies brain Corticosteroid Receptor expression and endocrine function in the fetal guinea pig
Brain Research, 1999Co-Authors: Rania Lingas, Farrah Dean, Stephen G. MatthewsAbstract:Abstract Modification of the fetal environment has been shown to program hypothalamo-pituitary-adrenal (HPA) development. Altered expression of brain Corticosteroid Receptors is thought to be central to this process. In the fetal guinea pig, rapid development of glucocorticoid Receptors (GR) and mineralocorticoid Receptors (MR) occurs in concert with rapid brain growth. Since nutrient availability has been associated with programming of endocrine function, we hypothesized that 48 h of maternal nutrient deprivation during rapid brain growth modifies the fetal endocrine environment and alters expression of GR and MR in the fetal brain. Pregnant guinea pigs were deprived of food (water available ad libitum) or fed normally on gestational days 50–51, and euthanized on gd52 (term=70 days). Nutrient deprivation caused intrauterine growth restriction (IUGR), though brain growth was protected. Fetal and maternal plasma cortisol was elevated in the deprived animals (p
Philip W Gold - One of the best experts on this subject based on the ideXlab platform.
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increased expression of corticotropin releasing hormone and vasopressin messenger ribonucleic acid mrna in the hypothalamic paraventricular nucleus during repeated stress association with reduction in glucocorticoid Receptor mrna levels
Endocrinology, 1995Co-Authors: Shinya Makino, Mark A Smith, Philip W GoldAbstract:Hypothalamic-pituitary-adrenal (HPA) responses remain intact or increase after chronic or repeated stress despite robust levels of circulating glucocorticoids that would be expected to restrain the responsiveness of the axis. The purpose of this study was to determine whether chronic stress altered Corticosteroid Receptor messenger RNA (mRNA) levels at any locus known to mediate glucocorticoid feedback on HPA function (i.e. hippocampus or hypothalamus), whether such effects were glucocorticoid dependent, and whether changes in Corticosteroid Receptor function could potentially contribute to the putative shift from corticotropin-releasing hormone (CRH) to arginine vasopressin (AVP) in the hypothalamic paraventricular nucleus (PVN) in the modulation of pituitary adrenal function occurring during chronic stress. We compared the stress responsiveness of sham-operated rats to that of adrenalectomized rats using a moderate dose of corticosterone (CORT) pellet replacement (ADX + CORT group). Acute immobilization...
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increased expression of corticotropin releasing hormone and vasopressin messenger ribonucleic acid mrna in the hypothalamic paraventricular nucleus during repeated stress association with reduction in glucocorticoid Receptor mrna levels
Endocrinology, 1995Co-Authors: Shinya Makino, Mark A Smith, Philip W GoldAbstract:Hypothalamic-pituitary-adrenal (HPA) responses remain intact or increase after chronic or repeated stress despite robust levels of circulating glucocorticoids that would be expected to restrain the responsiveness of the axis. The purpose of this study was to determine whether chronic stress altered Corticosteroid Receptor messenger RNA (mRNA) levels at any locus known to mediate glucocorticoid feedback on HPA function (i.e. hippocampus or hypothalamus), whether such effects were glucocorticoid dependent, and whether changes in Corticosteroid Receptor function could potentially contribute to the putative shift from corticotropin-releasing hormone (CRH) to arginine vasopressin (AVP) in the hypothalamic paraventricular nucleus (PVN) in the modulation of pituitary adrenal function occurring during chronic stress. We compared the stress responsiveness of sham-operated rats to that of adrenalectomized rats using a moderate dose of corticosterone (CORT) pellet replacement (ADX + CORT group). Acute immobilization caused a significant increase in CRH, but not AVP, mRNA levels in the parvocellular PVN in sham rats. The ADX + CORT group showed significantly greater increases in both CRH and AVP mRNA levels in the PVN compared to sham rats. These data indicate that PVN AVP mRNA levels are more sensitive to glucocorticoid negative feedback than are the levels of CRH mRNA. In repeated stress, the sham groups showed robust increases in PVN CRH and AVP mRNA levels despite high levels of plasma CORT. The rise in AVP mRNA levels was greater than that in CRH mRNA. Type II glucocorticoid Receptor mRNA in the hippocampus and PVN was decreased in the repeatedly stressed sham group. These data suggest a decrease in the CORT negative feedback restraint of PVN CRH and AVP mRNA levels repeated stress and a persistence of relatively greater responsiveness of AVP mRNA levels to CORT negative feedback. After repeated stress in ADX+CORT rats, both PVN CRH and AVP mRNA levels showed robust responses, with a relatively greater increase in AVP mRNA. These data indicate that a CORT-mediated decrease in hippocampal and hypothalamic glucocorticoid Receptor mRNA levels is not the only mechanism contributing to the maintenance of a robust HPA response after repeated stress. Similarly, we postulate that the relative shift from CRH to AVP in the PVN after repeated stress is mediated by both a greater sensitivity of AVP to CORT negative feedback and CORT-independent mechanisms.
Florian Holsboer - One of the best experts on this subject based on the ideXlab platform.
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polymorphisms in the fkbp5 gene region modulate recovery from psychosocial stress in healthy controls
European Journal of Neuroscience, 2008Co-Authors: Marcus Ising, Manfred Uhr, Susanne Lucae, Annamareike Depping, Anna Siebertz, Paul G Unschuld, S Kloiber, S Horstmann, Bertram Mullermyhsok, Florian HolsboerAbstract:Mood and anxiety disorders are considered stress-related diseases characterized by an impaired function of mineralocorticoid and glucocorticoid Receptors (MR and GR, respectively), the major regulatory elements of the hypothalamus-pituitary-adrenocortical (HPA) axis. A number of so-called chaperone proteins moderate the function of these Receptors. Genetic variations in one of these chaperones, FKBP5, were associated with antidepressant treatment response in depression and with a major risk-factor for the development of posttraumatic stress disorder. To further investigate the effect of FKPB5 polymorphisms on Corticosteroid Receptor-mediated HPA axis regulation we conducted the Trier Social Stress test, a standardized procedure to evaluate psychosocial stress response, in 64 healthy volunteers. We genotyped rs4713916, rs1360780 and rs3800737, the three single nucleotide polymorphisms (SNPs) in the FKBP5 region which had shown the strongest effect in previous studies. In addition, we evaluated the effects of the GR polymorphisms Bcl1 and N363S as well as the MR polymorphism I180V. Subjects homozygous for any of the FKBP5 variants displayed an incomplete normalization of the stress-elicited cortisol secretion. This was also observed following a second test additionally accompanied by an increased self-reported anxiety. Regarding GR and MR, only carriers of the Bcl1 variant displayed an altered cortisol response in the prognosticated direction. While Bcl1 was predominantly associated with anticipatory cortisol, homozygous carriers of the FKBP5 minor allele showed insufficient cortisol recovery and increased self-reported anxiety after psychosocial stress. This reaction pattern suggests that subjects carrying these variants are at risk of displaying chronically elevated cortisol levels after repeated stress constituting a risk factor for stress-related diseases.
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combined treatment with Corticosteroids and moclobemide favors normalization of hypothalamo pituitary adrenal axis dysregulation in relapsing remitting multiple sclerosis a randomized double blind trial
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Then F Bergh, Tania Kumpfel, A Grasser, Rainer Rupprecht, Florian Holsboer, Claudia TrenkwalderAbstract:Hyperresponsiveness of the hypothalamo-pituitary-adrenal (HPA) axis in multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system, is presumably due to diminished Corticosteroid Receptor function. It probably influences the immune response, but its clinical significance is not clear. Similar HPA dysregulation occurs in depression and is reversible with successful antidepressant treatment. We conducted a double blind, placebo-controlled trial to evaluate the neuroendocrine effect of cotreatment with the antidepressant moclobemide as an adjunct to oral Corticosteroids in MS. Twenty-one patients with definite relapsing-remitting MS (11 females, aged 33.9 +/- 2.0 yr; Expanded Disability Status Scale score of neurological impairment, 2.0--6.5) in acute relapse were treated with placebo (n = 13) or 300 mg moclobemide (reversible monoamine oxidase A inhibitor; n = 8) for 75 days. All received oral fluocortolone from day 7 on, and the dose was tapered until day 29. Effects were evaluated using the combined dexamethasone-CRH test and clinically on days 1, 30, and 75. At baseline, the HPA axis was mildly activated, comparably for treatment groups [area under the curve for cortisol (AUC-Cort), 213.8 +/- 76.8 arbitrary units in the moclobemide group vs. 225.8 +/- 65.1 in the steroid alone group; mean +/- SEM]. In a group of healthy controls with comparable demographic characteristics, the AUC-Cort was 107.4 +/- 14.1. Moclobemide cotreatment resulted in normalization of the HPA axis response, whereas the HPA system hyperresponse was maintained with steroids alone (AUC-Cort on day 30, 85.9 +/- 22.8 vs.177.1 +/- 68.5; on day 75, 111.0 +/- 46.0 vs. 199.2 +/- 64.6). The change in Expanded Disability Status Scale was comparable for both groups. Although Corticosteroids alone had no effect on the HPA response using the dexamethasone-CRH test, treatment with moclobemide combined with Corticosteroids favors normalization of the HPA response in relapsing-remitting MS.
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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.
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The Corticosteroid Receptor Hypothesis of Depression
Neuropsychopharmacology, 2000Co-Authors: Florian HolsboerAbstract:Signs and symptoms that are characteristic for depression include changes in the setpoint of the hypothalamic-pituitary-adrenocortical (HPA) system, which in the majority of these patients result in altered regulation of corticotropin (ACTH) and cortisol secretory activity. More refined analysis of the HPA system revealed that Corticosteroid Receptor (CR) signaling is impaired in major depression, resulting among other changes, in increased production and secretion of corticotropin-releasing hormone (CRH, also frequently abbreviated CRF) in various brain regions postulated to be involved in the causality of depression. This article summarizes the clinical and preclinical data, supporting the concept that impaired CR signaling is a key mechanism in the pathogenesis of depression. Mouse genetics, allowing for selective inactivation of genes relevant for HPA regulation and molecular pharmacology, dissecting the intracellular cascade of CR signaling, are the most promising future research fields, suited for identifying genes predisposing to depression. Focusing on these two research lines may also allow to gain insight into understanding how current antidepressants work and further, how more specific targets for future antidepressant drugs can be identified.
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the rationale for corticotropin releasing hormone Receptor crh r antagonists to treat depression and anxiety
Journal of Psychiatric Research, 1999Co-Authors: Florian HolsboerAbstract:Abstract Neuroendocrine studies strongly suggest that dysregulation of the hypothalamic–pituitary–adrenocortical (HPA) system plays a causal role in the development and course of depression. Whereas the initial mechanism resulting in HPA hyperdrive remains to be elucidated, evidence has emerged that Corticosteroid Receptor function is impaired in many patients with depression and in many healthy individuals at increased genetic risk for an depressive disorder. Assuming such impaired Receptor function, then central secretion of CRH would be enhanced in many brain areas, which would account for a variety of depressive symptoms. As shown in rats and also in transgenic mice with impaired glucocorticoid Receptor function, antidepressants enhance the signaling through Corticosteroid Receptors. This mechanism of action can be amplified through blocking central mechanisms that drive the HPA system. Animal experiments using antisense oligodeoxynucleotides directed against the mRNA of both CRH Receptor subtypes identified the CRH1 Receptor as the mediator of the anxiogenic effects of CRH. Studies in mouse mutants in which this Receptor subtype had been deleted extended these findings as the animals were less anxious than wild-type mice when experimentally stressed. Thus, patients with clinical conditions that are causally related to HPA hyperactivity may profit from treatment with a CRH1 Receptor antagonist.
Stephen D Mccormick - One of the best experts on this subject based on the ideXlab platform.
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11 deoxycortisol is a stress responsive and gluconeogenic hormone in a jawless vertebrate the sea lamprey petromyzon marinus
The Journal of Experimental Biology, 2021Co-Authors: Ciaran A Shaughnessy, Stephen D MccormickAbstract:Although Corticosteroid-mediated hepatic gluconeogenic activity in response to stress has been extensively studied in fishes and other vertebrates, there is little information on the stress response in basal vertebrates. In sea lamprey (Petromyzon marinus), a representative member of the most basal extant vertebrate group Agnatha, 11-deoxycortisol and deoxycorticosterone are the major circulating Corticosteroids. The present study examined changes in circulating glucose and 11-deoxycortisol concentrations in response to a physical stressor. Furthermore, the gluconeogenic actions of 11-deoxycortisol and deoxycorticosterone were examined. Within 6 h after exposure of larval and juvenile sea lamprey to an acute handling stress, plasma 11-deoxycortisol levels increased 15- and 6-fold, respectively, and plasma glucose increased 3- and 4-fold, respectively. Radiometric Receptor binding studies revealed that a Corticosteroid Receptor (CR) is present in the liver at lower abundance than other tissues (gill and anterior intestine) and that the binding affinity of the liver CR was similar for 11-deoxycortisol and deoxycorticosterone. Transcriptional tissue profiles indicate a wide distribution of cr transcription, kidney-specific transcription of steroidogenic acute regulatory protein (star), and liver-specific transcription of phosphoenolpyruvate carboxykinase (pepck). Ex vivo incubation of liver tissue with 11-deoxycortisol resulted in dose-dependent increases in pepck mRNA levels. Finally, intraperitoneal administration of 11-deoxycortisol and deoxycorticosterone demonstrated that only 11-deoxycortisol resulted in an increase in plasma glucose. Together, these results provide the first direct evidence for the gluconeogenic activity of 11-deoxycortisol in an Agnathan, indicating that Corticosteroid regulation of plasma glucose is a basal trait among vertebrates.
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regulation of gill cytosolic Corticosteroid Receptors in juvenile atlantic salmon interaction effects of growth hormone with prolactin and triiodothyronine
General and Comparative Endocrinology, 1998Co-Authors: J M Shrimpton, Stephen D MccormickAbstract:The potential effects of growth hormone (GH), prolactin (Prl), and triiodothyronine (T3) on gill Na+,K+-ATPase activity and Corticosteroid Receptor (CR) concentration (Bmax) and dissociation constant (Kd) were examined in juvenile Atlantic salmon (Salmo salar). Compared to controls, fish injected with GH (ovine, 5.0 μg g−1) had significantly greater gill Na+,K+-ATPase activity after 7 and 14 days. Gill CRBmaxandKdwere significantly elevated on day 7, but not day 14. T3also significantly increased CRBmax. The effect of GH on CRBmaxwas also additive with T3(5.0 μg g−1) treatment. There was a synergistic effect on CRBmaxwhen purified coho salmon GH (csGH, 0.1 μg g−1) was injected in combination with T3(1.6 μg g−1). Prl (ovine, 5.0 μg g−1; purified coho salmon, 0.1 μg g−1) did not significantly alter gill CRBmax. Although Prl limited the increase in CRBmaxby GH, the effect was not signicant. T3and Prl did not have an effect onKd. GH significantly increased gill Na+,K+-ATPase activity, T3administration did not have a significant effect, and Prl-treated fish had significantly lower gill Na+,K+-ATPase activity. The results indicate that T3acts additively with GH, while Prl has no effect in regulating CRBmax. An increase in cytosolic CR by GH and T3, but not Prl, may regulate gill responsiveness to cortisol and be an important mechanism in the endocrine control of physiological changes during the parr–smolt transformation.
Shinya Makino - One of the best experts on this subject based on the ideXlab platform.
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increased expression of corticotropin releasing hormone and vasopressin messenger ribonucleic acid mrna in the hypothalamic paraventricular nucleus during repeated stress association with reduction in glucocorticoid Receptor mrna levels
Endocrinology, 1995Co-Authors: Shinya Makino, Mark A Smith, Philip W GoldAbstract:Hypothalamic-pituitary-adrenal (HPA) responses remain intact or increase after chronic or repeated stress despite robust levels of circulating glucocorticoids that would be expected to restrain the responsiveness of the axis. The purpose of this study was to determine whether chronic stress altered Corticosteroid Receptor messenger RNA (mRNA) levels at any locus known to mediate glucocorticoid feedback on HPA function (i.e. hippocampus or hypothalamus), whether such effects were glucocorticoid dependent, and whether changes in Corticosteroid Receptor function could potentially contribute to the putative shift from corticotropin-releasing hormone (CRH) to arginine vasopressin (AVP) in the hypothalamic paraventricular nucleus (PVN) in the modulation of pituitary adrenal function occurring during chronic stress. We compared the stress responsiveness of sham-operated rats to that of adrenalectomized rats using a moderate dose of corticosterone (CORT) pellet replacement (ADX + CORT group). Acute immobilization...
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increased expression of corticotropin releasing hormone and vasopressin messenger ribonucleic acid mrna in the hypothalamic paraventricular nucleus during repeated stress association with reduction in glucocorticoid Receptor mrna levels
Endocrinology, 1995Co-Authors: Shinya Makino, Mark A Smith, Philip W GoldAbstract:Hypothalamic-pituitary-adrenal (HPA) responses remain intact or increase after chronic or repeated stress despite robust levels of circulating glucocorticoids that would be expected to restrain the responsiveness of the axis. The purpose of this study was to determine whether chronic stress altered Corticosteroid Receptor messenger RNA (mRNA) levels at any locus known to mediate glucocorticoid feedback on HPA function (i.e. hippocampus or hypothalamus), whether such effects were glucocorticoid dependent, and whether changes in Corticosteroid Receptor function could potentially contribute to the putative shift from corticotropin-releasing hormone (CRH) to arginine vasopressin (AVP) in the hypothalamic paraventricular nucleus (PVN) in the modulation of pituitary adrenal function occurring during chronic stress. We compared the stress responsiveness of sham-operated rats to that of adrenalectomized rats using a moderate dose of corticosterone (CORT) pellet replacement (ADX + CORT group). Acute immobilization caused a significant increase in CRH, but not AVP, mRNA levels in the parvocellular PVN in sham rats. The ADX + CORT group showed significantly greater increases in both CRH and AVP mRNA levels in the PVN compared to sham rats. These data indicate that PVN AVP mRNA levels are more sensitive to glucocorticoid negative feedback than are the levels of CRH mRNA. In repeated stress, the sham groups showed robust increases in PVN CRH and AVP mRNA levels despite high levels of plasma CORT. The rise in AVP mRNA levels was greater than that in CRH mRNA. Type II glucocorticoid Receptor mRNA in the hippocampus and PVN was decreased in the repeatedly stressed sham group. These data suggest a decrease in the CORT negative feedback restraint of PVN CRH and AVP mRNA levels repeated stress and a persistence of relatively greater responsiveness of AVP mRNA levels to CORT negative feedback. After repeated stress in ADX+CORT rats, both PVN CRH and AVP mRNA levels showed robust responses, with a relatively greater increase in AVP mRNA. These data indicate that a CORT-mediated decrease in hippocampal and hypothalamic glucocorticoid Receptor mRNA levels is not the only mechanism contributing to the maintenance of a robust HPA response after repeated stress. Similarly, we postulate that the relative shift from CRH to AVP in the PVN after repeated stress is mediated by both a greater sensitivity of AVP to CORT negative feedback and CORT-independent mechanisms.
