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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of the glucocorticoid receptor agonist RU-28362 on homosynaptic long-term depression (LTD) were examined in hippocampal slices obtained from adrenal-intact adult male rats. Field excitatory postsynaptic potentials were evoked by stimulation of the Schaffer collateral/commissural pathway and recorded in stratum radiatum of area CA1. Low-frequency stimulation (LFS) was delivered at LTD threshold (2 bouts of 600 pulses, 1 Hz, at baseline stimulation intensity). LFS of the Schaffer collaterals did not produce significant homosynaptic LTD in control slices. However, identical conditioning in the presence of the glucocorticoid receptor agonist RU-28362 (10 microM) produced a robust LTD, which was blocked by the selective glucocorticoid antagonist RU-38486. The LTD induced by glucocorticoid receptor activation was dependent on N-methyl-D-aspartate (NMDA) receptor activity, because the specific NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) blocked the facilitation. However, the facilitation of LTD was not due to a potentiation of the isolated NMDA receptor potential by RU-28362. The facilitation of LTD by RU-28362 was also blocked by coincubation of the L-type voltage-dependent calcium channel (VDCC) antagonist nimodipine. Selective activation of the L-type VDCCs by the agonist Bay K 8644 also facilitated LTD induction. Both nimodipine and D-AP5 were effective in blocking the facilitation of LTD by Bay K 8644. These results indicate that L-type VDCCs can contribute to NMDA-receptor-dependent LTD induction.
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PMID:Glucocorticoid receptor activation lowers the threshold for NMDA-receptor-dependent homosynaptic long-term depression in the hippocampus through activation of voltage-dependent calcium channels. 924 54

The proinflammatory cytokines which are released by activated accessory immune cells during the course of an infection have profound effects on the brain. These effects include activation of the hypothalamic-pituitary-adrenal axis, fever and behavioral depression. They are mediated by cytokines which are synthesized and released in the brain, in response to peripherally released cytokines. Glucocorticoids have potent regulatory effects on the synthesis of cytokines by activated macrophages and monocytes. These hormones are also able to regulate the synthesis and action of cytokines in the brain, as demonstrated by the sensitizing effects of adrenalectomy and the depressing effects of stress on the increased cytokine and interleukin-1 beta converting enzyme gene expression that occurs in response to lipopolysaccharide in mice. Preliminary experiments indicate that another way glucocorticoids can contribute to down regulation of the IL-1 system is by increasing the expression of the type II IL-1 receptor in the brain. The regulatory effects of glucocorticoids on cytokine expression in the brain have functional consequences, as demonstrated by the enhanced sensitivity of adrenalectomized animals to the behavioral actions of centrally administered LPS and IL-1. The effects of adrenalectomy are inhibited by compensation with a corticosterone implant and they are mimicked by administration of the type II glucocorticoid receptor, RU 38486. The regulatory role of glucocorticoids on the expression and action of cytokines in the brain makes these hormones and their mechanisms of action key targets for therapeutic interventions in psychopathology and neuropathology.
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PMID:Regulation of cytokine gene expression in the central nervous system by glucocorticoids: mechanisms and functional consequences. 926 51

Several studies with adrenalectomized rats have shown that the suppressive effects of exogenous corticosteroids on 5-hydroxytryptamine(1A) receptor function are mediated by the high-affinity mineralocorticoid receptor, rather than the lower affinity glucocorticoid receptor. In the present study, adrenally intact rats were subcutaneously implanted for six days with pellets containing a small amount of corticosterone, which leads to a flattening of the circadian rhythm in the level of circulating hormone. The peak in daily corticosterone is suppressed, the basal trough is increased, and the hormone levels remain at a constant value equivalent to the daily average of about 5 microg/dl, which is usually observed in rats. Accordingly, this regime of corticosterone treatment did not enhance exclusively glucocorticoid receptor-controlled parameters, such as the weight of the thymus. Effects involving mineralocorticoid receptor activation were enhanced, since reductions were observed in stress-induced plasma corticosterone levels and adrenal weight. 5-Hydroxytryptamine(1A) receptor messenger RNA levels were found to be suppressed by approximately 25% in the dentate gyrus of the hippocampus of these corticosterone pellet-implanted rats. This suppression was reflected in significantly reduced [3H]8-hydroxy-2-(di-n-propylamino)tetralin binding in the hippocampal region. We propose therefore that this suppressive effect on 5-hydroxytryptamine(1A) receptor expression involves enhanced occupation of mineralocorticoid receptors, under a condition of elevated basal trough corticosteroid levels as is commonly observed in human depression.
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PMID:Elevated basal trough levels of corticosterone suppress hippocampal 5-hydroxytryptamine(1A) receptor expression in adrenally intact rats: implication for the pathogenesis of depression. 928 45

The glucocorticoid receptor (GR) is a ligand-regulated transcription factor that in its unactivated form resides primarily in the cytoplasm. After being bound by steroid, the GR undergoes a conformational change and translocates to the nucleus, where it influences gene transcription. Because the GR mediates negative feedback exerted by circulating glucocorticoid hormones on the hypothalamic-pituitary-adrenal (HPA) axis, it has been hypothesized that abnormalities in GR expression and/or function may underlie the HPA axis hyperactivity described in patients with major depression. In further support of this hypothesis, animal studies have shown that long term in vivo treatment with antidepressants enhances glucocorticoid feedback inhibition, possibly through a direct effect on the GR. To examine this latter possibility, we evaluated translocation of the GR from the cytoplasm to the nucleus after 24-hr in vitro treatment of L929 cells (mouse fibroblasts) with the tricyclic antidepressant desipramine (0.1-10 microM) in the presence or absence of the synthetic steroid dexamethasone. In addition, GR-mediated gene transcription was measured with the use of L929 cells stably transfected with the mouse mammary tumor virus-chloramphenicol acetyltransferase reporter gene. Desipramine was found to (i) induce GR translocation from the cytoplasm to the nucleus in the absence of steroids (with no effect alone on GR-mediated gene transcription) and (ii) potentiate dexamethasone-induced GR translocation and dexamethasone-induced GR-mediated gene transcription. Treatment with desipramine for 24-96 hr had no effect on the expression of GR protein as measured by cytosolic radioligand receptor binding. We suggest that one important aspect of the effects of antidepressants in vivo may be to facilitate GR-mediated feedback inhibition on the HPA axis, by facilitating GR translocation and function, and thereby reverse glucocorticoid hypersecretion in depression.
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PMID:Steroid-independent translocation of the glucocorticoid receptor by the antidepressant desipramine. 938 19

The activity of the hippocampus is modulated by a serotonergic projection from the midbrain. Corticosteroids regulate the activity of this raphe-hippocampal system in various ways. These effects are differentially mediated via two types of central corticosteroid receptor types, the high-affinity mineralocorticoid receptor (MR), and the lower affinity glucocorticoid receptor (GR). Under physiological fluctuations of corticosteroid concentrations, predominantly MR-mediated effects suppress the activity of the raphe-hippocampal system, notably serotonin (5-HT)1A receptor-related activity: 5-HT1A receptors are down-regulated, and the cellular response to 5-HT1A receptor activation is attenuated. Transiently increased concentrations of corticosteroids, as induced by stress, result in combined occupation of both MR and GR, and allow increased activity of the raphe-hippocampal system. Stimulatory actions of corticosteroids involving GR occupation include increased responsiveness of hippocampal neurons to 5-HT1A receptor stimulation, attenuated autoinhibition of 5-HT, and a permissive effect on stress-induced increases in 5-HT release. Under (pathological) conditions of chronically elevated corticosteroid concentrations, however, serotonergic neurotransmission is impaired. Human depression is an important example of a condition of combined hypercorticism and an apparent hypoactivity of serotonergic transmission. Deficiency of brain GR function may be genetically determined or acquired by stress. It is proposed that the balance of MR/GR activation can be altered by chronic (stress-related) changes of corticosteroid concentrations, in combination with glucocorticoid feedback resistance. Such an imbalance would lead to a relative dominance of MR-mediated suppressive effects on the activity of the raphe-hippocampal system, which may be a biologically relevant aspect of depression.
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PMID:Corticosterone and serotonergic neurotransmission in the hippocampus: functional implications of central corticosteroid receptor diversity. 944 79

Learning and memory are exquisitely sensitive to behavioral stress, but the underlying mechanisms are still poorly understood. Because activity-dependent persistent changes in synaptic strength are believed to mediate memory processes in brain areas such as the hippocampus we have examined the means by which stress affects synaptic plasticity in the CA1 region of the hippocampus of anesthetized rats. Inescapable behavioral stress (placement on an elevated platform for 30 min) switched the direction of plasticity, favoring low frequency stimulation-induced decreases in synaptic transmission (long-term depression, LTD), and opposing the induction of long-term potentiation by high frequency stimulation. We have discovered that glucocorticoid receptor activation mediates these effects of stress on LTD and long-term potentiation in a protein synthesis-dependent manner because they were prevented by the glucocorticoid receptor antagonist RU 38486 and the protein synthesis inhibitor emetine. Consistent with this, the ability of exogenously applied corticosterone in non-stressed rats to mimic the effects of stress on synaptic plasticity was also blocked by these agents. The enablement of low frequency stimulation-induced LTD by both stress and exogenous corticosterone was also blocked by the transcription inhibitor actinomycin D. Thus, naturally occurring synaptic plasticity is liable to be reversed in stressful situations via glucocorticoid receptor activation and mechanisms dependent on the synthesis of new protein and RNA. This indicates that the modulation of hippocampus-mediated learning by acute inescapable stress requires glucocorticoid receptor-dependent initiation of transcription and translation.
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PMID:Glucocorticoid receptor and protein/RNA synthesis-dependent mechanisms underlie the control of synaptic plasticity by stress. 950 Dec 41

Patients with depression frequently have symptom clusters which point strongly to involvement of the hypothalamic-pituitary-adrenal (HPA) system as a relay station between neurocircuitries in the brain and peripheral hormone and autonomic nervous function. It has been proposed that this increased, state-dependent hyperactivity of the HPA-system in depression is probably initiated and/or maintained by the combination of enhanced central production of CRH and desensitization of the binary, glucocorticoid receptor binding system in the hippocampus, which is the central regulator of HPA system activity. In a first series of studies a refined neuroendocrine test to probe the integrity of HPA system status--the combined dexamethasone suppression/CRH challenge (DEX/CRH) test--was developed and the differential effects of aging and depressed psychopathology on DEX/CRH test outcome were described. In a second set of studies, the chronological relationship between improvement of psychopathology in depressed patients treated with antidepressants and normalization of the disturbed HPA system function in these patients was further elucidated. Given the evidence from animal studies, we conclude that antidepressants induce an up-regulation of hippocampal glucocorticoid receptor mRNA concentration, thus amplifying the negative feedback effect of glucocorticoids. This then results in the normalization of DEX/CRH test results observed in the depressed patients in our study. We further conclude that dampening of HPA system hyperactivity in depression by means of antidepressants is a conditio sine qua non for successful improvement of psychopathology.
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PMID:Anna-Monika-Prize paper. The hypothalamic-pituitary-adrenal system in depression. 952 78

This review focuses on experiments in humans examining the regulation of the hypothalamo-pituitary-adrenal (HPA) system during nocturnal sleep. The HPA system is a most important mediator of the organism's response to stress. The early phase of nocturnal sleep dominated by extended epochs of slow wave sleep (SWS), is the only time of day in which secretory activity of this axis is subject to a pronounced and persistent inhibition resulting in minimum concentrations of ACTH and cortisol. During late sleep predominated by rapid eye movement (REM) sleep. HPA secretory activity reaches a diurnal maximum. Comparison of the response to administration of exogenous secretagogues of ACTH in men during sleep and nocturnal wakefulness indicated that early sleep, and in particular SWS, is associated with an inhibition of pituitary-adrenocortical responsiveness, which is presumably due to hypothalamic secretion of an as yet unknown release inhibiting factor of ACTH. Pituitary-adrenocortical responsiveness during early sleep was disinhibited after canrenoate which is a selective blocker of mineralocorticoid receptors (MR) located primarily in limbic-hippocampal structures. Hippocampal neuronal networks are known to integrate corticosteroid feedback via both, the MR and the classical glucocorticoid receptor (GR). Prevailing MR related activity in this network seems to act as a trigger for the inhibition of the HPA system. During early sleep, the same hippocampal network appears to be concurrently involved in the formation of declarative memory. Activation of GR after administration of dexamethasone completely blocked the formation of declarative memory during early sleep, indicating that the inhibition of HPA secretory activity is a necessary prerequisite for this memory process. Dysfunction of the described neuro-endocrine mode of regulation during early sleep is present in patients with Cushing's disease, in patients with severe depression and in aged humans. All of these groups show insufficient inhibition of HPA secretory activity particular prominent during early sleep, and reduced SWS in concert with impairments of declarative memory function. First clinical trials suggest that this trias of symptoms may benefit from intranasal treatment with neuropeptides like vasopressin and growth hormone releasing hormone.
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PMID:Hypothalamus-pituitary-adrenal activity during human sleep: a coordinating role for the limbic hippocampal system. 971 Mar 53

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.
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PMID:The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. 1036 86

Recent research suggests that antidepressants exert their clinical action in depression via the restoration of glucocorticoid receptor (GR) function with a subsequent normalization of the altered feed-back regulation of the hypothalamic-pituitary adrenocortical (HPA) system. We, therefore, studied the effects of amitriptyline, a standard antidepressant, and of the glucocorticoid dexamethasone, which has recently been reported to possess antidepressive properties, on glucocorticoid receptor mRNA (GR-mRNA) derived from blood cells of healthy male volunteers. Whole blood samples were exposed in vitro for 24 h to amitriptyline and dexamethasone, the mRNA was extracted, transcripts of the 'house-keeping gene' glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the GR-gene were subjected to reverse transcriptase-polymerase chain reaction (RT-PCR) and semiquantitatively determined by subsequent densitometry. In a concentration of 10 nM, amitriptyline induced a significant increase in GR-mRNA (GR/GAPDH ratio) to 186 +/- 31% of the control condition, while a concentration of 10 microM of amitriptyline resulted in an increase of GR-mRNA (GR/GAPDH ratio) to 165 +/- 36%. Dexamethasone also up-regulated blood cell GR-mRNA (GR/GAPDH ratio) levels at a concentration of 10 nM to 184 +/- 29%, whereas an incubation with 10 microM apparently resulted in toxic effects on blood cells with a decreased amount of total mRNA samples recovered. In conclusion, we here show an increase of GR-mRNA in human blood cells after treatment with amitriptyline and dexamethasone, pointing to a direct action of these substances on GR-gene expression in a human system.
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PMID:Regulation of glucocorticoid receptor-mRNA in human blood cells by amitriptyline and dexamethasone. 1040 68


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