Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dysregulation of the serotonergic system and abnormalities of the hypothalamic-pituitary-adrenal axis function have been implicated to be involved in neuropsychiatric disorders. Serotonin-1A receptors have been shown to be suppressed by corticosteroid hormones in a variety of animal studies. This effect may play a central role in the pathophysiology of depression. However, little is known about the molecular mechanism underlying this suppressive effect of corticosteroids. Here, we show by functional analysis of the promoter region of the rat serotonin-1A receptor gene that two NF-kappaB elements in the promoter contribute to induced transcription of the rat serotonin-1A receptor gene. Furthermore, we show that corticosteroids repress this NF-kappaB-mediated induction of transcription. Remarkably, we observed that only the glucocorticoid receptor and not the mineralocorticoid receptor was able to mediate this repressive effect of corticosteroids. We argue that negative cross-talk between the glucocorticoid receptor and NF-kappaB may provide a basis for the molecular mechanism underlying the negative action of corticosteroids on serotonin signaling in the brain.
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PMID:Regulation of the rat serotonin-1A receptor gene by corticosteroids. 1062 80

Rifampicin, an antibiotic widely used in tuberculosis therapy, is known to exert psychotropic side effects in some patients. Recently, rifampicin has been reported to activate the glucocorticoid receptor (GR) in human hepatocytes. Because there is evidence that increased levels of glucocorticoids may induce cognitive impairment, sometimes culminating in depression, the side effects of rifampicin may result from GR activation in central nerve cells. Therefore, we used reporter gene assays to determine whether rifampicin displays glucocorticoid-like effects in human neuroblastoma SK-N-MC cells or mouse hippocampal HT22 cells. Rifampicin was unable to elicit any detectable transactivation of GR in both cell types, whereas cortisol or dexamethasone led to a potent transcriptional response. Rifampicin was also inactive in the same HepG2 cell line that was originally used to demonstrate the effect of rifampicin on GR. Moreover, rifampicin was unable to compete with dexamethasone for binding to GR. Finally, by blocking the multidrug resistance P-glycoprotein transporter (a xenobiotic extrusion pump) with verapamil or cyclosporin A, we excluded the possibility that the lack of effect by rifampicin was due to its export from the cell. Our results establish that rifampicin does not activate GR, and rule out the hypothesis that the psychotropic side effects of rifampicin treatment are a consequence of GR activation.
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PMID:Rifampicin is not an activator of glucocorticoid receptor. 1072 19

Electroconvulsive shock (ECS) therapy is considered to be an effective treatment for depression, but its mechanism of action is still unknown. We investigated the effect of chronic ECS in rats treated for 14 days with dexamethasone (Dex), a glucocorticoid receptor agonist. Chronic injection of sesame oil decreased body weight change and increased serotonin (5-HT)-2A receptor number and DOI (5-HT-2A, 2C receptor agonist)-induced wet-dog shake (WDS) behaviors. Dex treatment for 14 days decreased body weight of rats, but repeated ECS did not reverse this decrease. Dex also abolished plasma corticosterone levels, and ECS failed to restore these levels. These results indicate that chronic ECS does not antagonize the effect of Dex. The treatment with Dex increased 5-HT-2A receptor binding density of rat frontal cortex and the number of DOI-induced WDS behaviors. Chronic ECS reduced the enhanced WDS behaviors by Dex but had little effect on receptor density. These results suggest that chronic ECS might suppress 5-HT-2A receptor function at the postreceptor signaling level rather than at the receptor itself, without changing HPA axis function in Dex-treated rats.
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PMID:Chronic electroconvulsive shock decreases (+/-) 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI)-induced wet-dog shake behaviors of dexamethasone-treated rats. 1073 22

Depression has been associated with impaired mineralocorticoid receptor function, restrained glucocorticoid receptor feedback at the level of the hypothalamic-pituitary-adrenal (HPA) axis, raised cortisol level and increased corticotropin-releasing factor activity, which may act in concert to induce the signs and symptoms of the disorder. Pre-clinical and clinical evidence suggests that both genetic and environmental factors contribute to the development of these HPA axis abnormalities in depressed patients. Support for this view derives from models using genetically modified animals and/or chronic stress exposure at different developmental stages, although all of the current approaches have to be viewed within their limitations to model the disease. However, both animal and human studies challenging the HPA system show at least some neuroendocrine and behavioural changes comparable to those seen in depression, suggesting that some of the depressive symptoms can be attributed to HPA axis hyperactivity. Moreover, normalization of the neuroendocrine function following chronic antidepressant drug treatment seems to be a prerequisite for stable remission of depressive psychopathology, i.e. that normalization of HPA function is critical for relief of the clinical symptomatology of this disorder.
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PMID:Glucocorticoids and depression. 1090 17

1. Antidepressant drugs are known to inhibit some changes evoked by glucocorticoids, as well as a hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis, often observed in depression. 2. The aim of present study was to investigate effects of various antidepressant drugs on the glucocorticoid-mediated gene transcription in fibroblast cells, stably transfected with an MMTV promoter (LMCAT cells). 3. The present study have shown that antidepressants (imipramine, amitriptyline, desipramine, fluoxetine, tianeptine, mianserin and moclobemide), but not cocaine, inhibit the corticosterone-induced gene transcription in a concentration- and a time-dependent manner. 4. Drugs which are known to augment clinical effects of medication in depressed patients (lithium chloride, amantadine, memantine), do not affect the inhibitory effects of imipramine on the glucocorticoid receptor (GR)-mediated gene transcription. 5. Inhibitors of phospholipase C (PLC), protein kinase C (PKC), Ca(2+)/calmodulin-dependent protein kinase (CaMK) and antagonists of the L-type Ca(2+) channel also inhibit the corticosterone-induced gene transcription. 6. Inhibitors of protein kinase A (PKA) and protein kinase G (PKG) are without effect on the GR-induced gene transcription. 7. Phorbol ester (an activator of PKC) attenuates the inhibitory effect of imipramine on the GR-induced gene transcription. 8. Imipramine decreases binding of corticosterone-receptor complex to DNA. 9. It is concluded that antidepressant drugs inhibit the corticosterone-induced gene transcription, and that the inhibitory effect of imipramine depends partly on the PLC/PKC pathway.
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PMID:Antidepressant drugs inhibit glucocorticoid receptor-mediated gene transcription - a possible mechanism. 1090 80

Reciprocal interactions between central 5-HT system and hypothalamo-pituitary-adrenal (HPA) axis are of particular relevance with regard to depression, in which alterations of both systems have been evidenced. In order to further explore these interactions, two models of mutant mice have been used. They consisted of knock-out mice lacking the 5-HT transporter (5-HTT-/-) and of transgenic mice with impaired glucocorticoid receptor (GR-i) expression. Under control conditions. the functional properties of 5-HT(1A) autoreceptors in GR-i mice were as in their paired wild-type. However, both chronic stress and long term treatment with fluoxetine induced abnormal adaptive changes in 5-HT(1A) autoreceptor functioning in GR-i mice. On the other hand, a marked desensitization of 5-HT(1A) autoreceptors was found in 5-HTT-/- mice as compared with paired wild-type animals, and this phenomenon was further enhanced by exposure to stressful conditions. These data show that alterations of HPA axis at the gene level has consequences on 5-HT neurotransmission, and reciprocally, that 5-HTT knock-out affects HPA-dependent responses to stress.
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PMID:5-HT-HPA interactions in two models of transgenic mice relevant to major depression. 1105 94

A reduction in glucocorticoid receptor (GR) function leads to hippocampus-dependent allocentric spatial learning deficits, altered novelty exploration and disrupted hippocampal long-term potentiation (LTP) in transgenic mice expressing a GR antisense construct. After continuous long-term treatment of these mice with moclobemide (a reversible inhibitor of monoamine oxidase A), spatial navigation performance but not accuracy improved during initial acquisition. These changes were associated with a shift of the threshold for the induction of hippocampal LTP at low stimulation frequencies. Moreover, novel object exploration increased in both control and transgenic animals following long-term treatment with moclobemide. These findings open the possibility that antidepressants might improve hippocampal function under conditions of impaired stress hormone regulation, and that these drugs might in part act through this mechanism to attenuate cognitive deficiency in disorders such as depression.
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PMID:Effects of the monoamine oxidase A inhibitor moclobemide on hippocampal plasticity in GR-impaired transgenic mice. 1128 54

Exposure to chronic stress is thought to play an important role in the etiology of depression. In this disorder, a disrupted negative feedback response to exogenous glucocorticoids on cortisol secretion has been indicated. However, the regulation of glucocorticoid negative feedback by chronic stress is not fully understood. In the present study, we investigated the effects of chronic stress administered by water immersion and restraint (2 h/day) for four weeks on the glucocorticoid feedback in rats. In the acutely (one-time) stressed rats, the basal plasma corticosterone (CORT) level was markedly elevated, remained at high levels for 5 h after the termination of stress, and then decreased. In the chronically stressed rats, the CORT level was initially elevated similarly, but rapidly decreased at 2 h. In the dexamethasone (DEX) suppression test, the peak CORT level in response to stress was not suppressed by DEX in the acutely stressed rats, but was significantly suppressed in the chronically stressed rats. In contrast, the suppressive effects of DEX on the basal CORT secretion in naive rats were attenuated in the chronically stressed rats. In the chronically stressed hippocampus, which plays an important role in the regulation of the glucocorticoid feedback response, the binding of [3H]DEX was decreased and the increased response of activator protein-1 induced by acute stress was abolished. These results suggest that chronic stress induces a hypersuppressive state for induced CORT secretion in response to acute stress, which is caused by partial habituation, coping, and adaptation to the stressor, whereas it induces a hyposuppressive state for the basal CORT secretion, which is caused by glucocorticoid receptor downregulation. These mechanisms may be involved in the stress-induced neural abnormalities observed in depression.
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PMID:Chronic stress differentially regulates glucocorticoid negative feedback response in rats. 1133 30

Impaired corticosteroid receptor signaling is a key mechanism in the pathogenesis of stress-related psychiatric disorders such as depression and anxiety. Since in vivo expression and functional studies of corticosteroid receptors are not feasible in the human central nervous system, such analyses have to be done in animal models. Transgenic mice with mutations of corticosteroid receptors are promising tools, which allow us to investigate the role of these proteins in the pathogenesis of symptoms characteristic for depression and anxiety. This review summarizes the neuroendocrinological and behavioral findings that have been obtained in six different mouse strains with specific mutations that influence the expression or the function of the glucocorticoid or the mineralocorticoid receptor (MR). The analyses of these mice helped to define molecular concepts of how corticosteroid receptors regulate the activity of the hypothalamic-pituitary-adrenal (HPA) system. Furthermore, some of these mutant mice exhibited characteristic alterations in behavioral tests for anxiety and despair. However, so far, none of the mouse strains described here can be viewed as an animal model of a specific psychiatric disease defined by common diagnostic criteria. Using high throughput technologies for the identification of genes regulated by glucocorticoid receptor (GR) and MR in brain areas responsible for specific symptoms of stress-related disorders will yield potential new drug targets for the treatment of depression and anxiety.
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PMID:Mice with targeted mutations of glucocorticoid and mineralocorticoid receptors: models for depression and anxiety? 1156 14

The rationale for treating psychotic major depression with glucocorticoid receptor (GR) antagonists is reviewed. Five patients with psychotic major depression were given 600 mg of mifepristone in a 4-day, double-blind, placebo-controlled crossover study. All the patients completed the protocol and adverse effects were not observed or reported. All of the five patients showed substantial improvements in their Hamilton Rating Scale for Depression scores while they were receiving mifepristone, and four of the five patients showed substantial improvement in their Brief Psychiatric Rating Scale scores. Little, if any, improvement was seen with placebo. These preliminary results suggest that short-term use of GR antagonists may be effective in the treatment of psychotic major depression and that additional study, perhaps using higher doses or more treatment days, seems warranted.
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PMID:Rapid reversal of psychotic depression using mifepristone. 1159 77


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