Man, society, and the failure of politics

Lewin, Leif

doi:10.1080/08913819808443480

Cited by 13 publications

(13 citation statements)

References 10 publications

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“…At lower corticosterone levels MR activation alone downregulates 5-HT1A receptors and suppresses of serotonin-related activity in the raphe-hippocampal system. Transient increases in glucocorticoid concentrations producing GR occupation rapidly increases the ability for hippocampal neurons to respond to 5-HT1A receptor stimulation, attenuates 5-HT autoinhibition, and facilitates stress-induced increases in 5-HT release, in part by increasing calcium influx and depolarizing the neurons (234,298). These concentrations also bind MR which through transrepression of the 5-HT1A receptor promoter by the MR:GR heterodimer, restores normal 5-HT1A receptor signaling after an appropriate delay and allows the brain to adapt to stress (343).…”

Section: Pathophysiological Implications Of Inappropriate Mr Activationmentioning

confidence: 99%

“…These concentrations also bind MR which through transrepression of the 5-HT1A receptor promoter by the MR:GR heterodimer, restores normal 5-HT1A receptor signaling after an appropriate delay and allows the brain to adapt to stress (343). However, chronic stress leads to chronic heterodimer formation and repression of 5-HT1A receptor transcription and depression-related behavior that led to the development of the selective serotonin reuptake inhibitors in use today (242, 298). As described in the section on epigenetic modifications of the MR and GR, chronic stress produces in rats many of the same biochemical changes found in depression (426).…”

Section: Pathophysiological Implications Of Inappropriate Mr Activationmentioning

confidence: 99%

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The Multifaceted Mineralocorticoid Receptor

Gómez-Sánchez

2014

Comprehensive Physiology

274

224

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The primary adrenal cortical steroid hormones, aldosterone, and the glucocorticoids cortisol and corticosterone, act through the structurally similar mineralocorticoid (MR) and glucocorticoid receptors (GRs). Aldosterone is crucial for fluid, electrolyte, and hemodynamic homeostasis and tissue repair; the significantly more abundant glucocorticoids are indispensable for energy homeostasis, appropriate responses to stress, and limiting inflammation. Steroid receptors initiate gene transcription for proteins that effect their actions as well as rapid non-genomic effects through classical cell signaling pathways. GR and MR are expressed in many tissues types, often in the same cells, where they interact at molecular and functional levels, at times in synergy, others in opposition. Thus the appropriate balance of MR and GR activation is crucial for homeostasis. MR has the same binding affinity for aldosterone, cortisol, and corticosterone. Glucocorticoids activate MR in most tissues at basal levels and GR at stress levels. Inactivation of cortisol and corticosterone by 11β-HSD2 allows aldosterone to activate MR within aldosterone target cells and limits activation of the GR. Under most conditions, 11β-HSD1 acts as a reductase and activates cortisol/corticosterone, amplifying circulating levels. 11β-HSD1 and MR antagonists mitigate inappropriate activation of MR under conditions of oxidative stress that contributes to the pathophysiology of the cardiometabolic syndrome; however, MR antagonists decrease normal MR/GR functional interactions, a particular concern for neurons mediating cognition, memory, and affect.

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Section: Pathophysiological Implications Of Inappropriate Mr Activationmentioning

confidence: 99%

Section: Pathophysiological Implications Of Inappropriate Mr Activationmentioning

confidence: 99%

The Multifaceted Mineralocorticoid Receptor

Gómez-Sánchez

2014

Comprehensive Physiology

274

224

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“…When circulating levels of corticosterone are the lowest (early morning in nocturnal species like mice), 70–95% of MR are occupied, whereas GR are activated mainly by higher circulating levels of corticosterone (in the evening or during stress). Although the effects of ADX are usually explained by the suppression of the tonic effects of MR, some of the previously cited effects observed after ADX were reversed by the GR agonist dexamethasone but not by the MR agonist aldosterone [6, 7]. …”

Section: Introductionmentioning

confidence: 99%

“…Although some authors reported no change in indices of the basal metabolism of serotonin (5-hydroxytryptamine, 5-HT) in the hippocampus, cortex or striatum after adrenalectomy (ADX) [1, 2], others, using different recovery periods after surgery, showed that removal of corticosterone reduces indices of basal 5-HT synthesis and turnover in the brain stem where the raphe nuclei which contain the serotoninergic cell bodies are located and also in the hippocampus and hypothalamus [3, 4, 5]. Moreover, many studies reported that basal circulating corticosterone levels exert inhibitory effects on mRNA expression and/or binding characteristics and functions of 5-HT 1A , 5-HT 1B and 5-HT 2C receptors, particularly in the hippocampus, and some of these effects could be the consequence of corticosterone-induced changes in 5-HT turnover [6, 7]. The effects of corticosterone are mediated by two types of receptors: the mineralocorticoid receptors (MR) and the glucocorticoid receptors (GR) which bind corticosterone with a 5- to 10-fold lower affinity than MR.…”

Section: Introductionmentioning

confidence: 99%

Regional Serotonin Metabolism under Basal and Restraint Stress Conditions in the Brain of Transgenic Mice with Impaired Glucocorticoid Receptor Function

et al. 1999

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Transgenic (TG) mice deficient in glucocorticoid receptors (GR) were used in order to study the effects of a reduced GR function on adrenocorticotropin hormone and corticosterone plasma levels and on serotonin metabolism in different brain areas under basal resting conditions, after a 30-min restraint stress and 60 min after the end of the restraint stress. There was no difference in basal or stress-induced levels of either adrenocorticotropin hormone or corticosterone in control and TG mice, but the return of adrenocorticotropin hormone to basal values after the end of the stress was delayed in TG mice. Under basal conditions, the ratio 5-hydroxyindoleacetic acid/5-hydroxytryptamine was decreased only in the hippocampus of TG mice compared to controls. In the brain stem, the ratio 5-hydroxyindoleacetic acid/5-hydroxytryptamine increased compared to basal values after a 30-min restraint stress and values were still high 60 min after the end of the restraint stress in both control and TG mice. In the hippocampus, the ratio 5-hydroxyindoleacetic acid/5-hydroxytryptamine increased at the end of the stress and returned to basal levels 60 min later in control mice, whereas there was no change at the end of the stress but an increase 60 min later in TG mice. Finally there was no change in serotonin metabolism in the cortex, striatum or hypothalamus in either group or situation. Our results support the hypothesis of a tonic activation of serotonin turnover by corticosterone through GR in the mouse hippocampus. Moreover, stress-induced stimulation of serotonin metabolism in the brain stem and hippocampus appears to be delayed in TG mice compared to control mice. These results are particularly relevant for mood disorders such as depression where alterations of serotoninergic transmission might be secondary to an impairment of GR functions.

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“…It is proposed that the balance of mineralocorticoid/glucocorticoid receptor activation can be altered by chronic changes of corticosteroid concentrations in combination with glucocorticoid feedback resistance. Such an imbalance would lead to a relative dominance of mineralocorticoid-receptor-mediated suppressive effects on the activity of the raphe-hippocampal system, which may be a biologically relevant aspect of depression [5]. However, the data regarding corticosteroid control of 5-HT receptors, other than 5-HT 1A , are scarce and contradictory.…”

Section: Introductionmentioning

confidence: 99%

Central 5-Hydroxytryptamine-2A Receptor Expression in Transgenic Mice Bearing a Glucocorticoid Receptor Antisense

Cyr

Charbonneau²,

Morissette³

et al. 2001

Neuroendocrinology

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Transgenic mice bearing a transgene coding for a glucocorticoid receptor antisense mRNA that partially blocks glucocorticoid receptor expression were used to investigate the long-term effect of hypothalamic-pituitary-adrenal dysfunction on brain 5-hydroxytryptamine-2A (5-HT_2A) receptor expression. The brain 5-HT_2A receptor mRNA levels in transgenic mice were measured by in situ hybridization and compared to those in control mice. We also studied the effect of a 3-week treatment with fluoxetine on brain 5-HT_2A receptor expression in the transgenic mice. No difference in 5-HT_2A mRNA levels was observed between transgenic and control mice in cortical or striatal regions, and fluoxetine treatment was without effect. No difference in hypothalamic 5-HT_2A mRNA levels was observed between transgenic and control mice, while fluoxetine treatment increased these levels in both transgenic as well as in the hypothalamic ventromedial and paraventricular nuclei of control mice. 5-HT_2A receptor mRNA levels were similar in hippocampal CA1 and CA2 subregions of control and transgenic, but were lower in the CA3 and CA4 subregions of transgenic mice. Fluoxetine had no effect on 5-HT_2A mRNA levels of transgenic mice but reduced control mouse 5-HT_2A receptor mRNA levels in the CA3 subregion. These results suggest that impaired glucocorticoid receptor function can affect hippocampal 5-HT_2A receptor expression in transgenic mice and that this is not corrected by fluoxetine treatment.

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Man, society, and the failure of politics

Cited by 13 publications

References 10 publications

The Multifaceted Mineralocorticoid Receptor

The Multifaceted Mineralocorticoid Receptor

Regional Serotonin Metabolism under Basal and Restraint Stress Conditions in the Brain of Transgenic Mice with Impaired Glucocorticoid Receptor Function

Central 5-Hydroxytryptamine-2A Receptor Expression in Transgenic Mice Bearing a Glucocorticoid Receptor Antisense

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