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)

Various classes of antidepressant drugs with distinct pharmacologic actions are differentially effective in the treatment of classic melancholic depression--characterized by pathological hyperarousal and atypical depression--associated with lethargy, hypersomnia, and hyperphagia. All antidepressant agents exert their therapeutic efficacy only after prolonged administration. In situ hybridization histochemistry was used to examine in rats the effects of short-term (2 weeks) and long-term (8 weeks) administration of 3 different classes of activating antidepressant drugs which tend to be preferentially effective in treating atypical depressions, on the expression of central nervous system genes thought to be dysregulated in major depression. Daily administration (5 mg/kg, i.p.) of the selective 5-hydroxytryptophan (5-HT) reuptake inhibitor fluoxetine, the selective alpha 2-adrenergic receptor antagonist idazoxan, and the nonspecific monoamine oxidase A and B inhibitor phenelzine increased tyrosine hydroxylase mRNA levels by 70-150% in the locus coeruleus after 2 weeks of drug and by 71-115% after 8 weeks. The 3 drugs decreased corticotropin-releasing hormone mRNA levels by 30-48% in the paraventricular nucleus of the hypothalamus. The decreases occurred at 8 weeks but not at 2 weeks. No consistent change in steroid hormone receptor mRNA levels was seen in the hippocampus with the 3 drugs, but fluoxetine and idazoxan increased the level of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA, respectively, after 8 weeks of drug administration. Proopiomelanocortin (POMC) mRNA levels in the anterior pituitary and plasma adrenocorticotropic-hormone (ACTH) levels were not altered after 2 or 8 weeks of drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications. 135 83

The hippocampus receives major noradrenergic and serotoninergic (5-HT) innervations which interact with corticosteroid-sensitive cells. However, the subregional localization of these actions and the corticosteroid receptor types involved have not been defined and current ligand binding techniques for estimating corticosteroid receptors are hampered by several methodological limitations. We have developed in situ hybridization histochemical techniques to allow specific and sensitive estimation of glucocorticoid (GR) and mineralocorticoid receptor (MR) mRNA expression in rat hippocampus. Investigation of the effects of 5,7-dihydroxytryptamine lesions of 5-HT neurons showed significantly reduced GR and MR mRNA expression in some hippocampal subregions. Both abnormal 5-HT neurotransmission and excessive corticosteroid secretion are associated with major affective disorder, particularly depression. The crucial interaction between these two systems may occur, at least in part, at the level of regulation of hippocampal corticosteroid receptor expression.
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PMID:Use of in situ hybridization to investigate the regulation of hippocampal corticosteroid receptors by monoamines. 165 90

Imipramine is the prototypic tricyclic antidepressant utilized in the treatment of major depression and exerts its therapeutic efficacy only after prolonged administration. We report a study of the effects of short-term (2 wk) and long-term (8 wk) administration of imipramine on the expression of central nervous system genes among those thought to be dysregulated in imipramine-responsive major depression. As assessed by in situ hybridization, 8 wk of daily imipramine treatment (5 mg/kg, i.p.) in rats decreased corticotropin-releasing hormone (CRH) mRNA levels by 37% in the paraventricular nucleus (PVN) of the hypothalamus and decreased tyrosine hydroxylase (TH) mRNA levels by 40% in the locus coeruleus (LC). These changes were associated with a 70% increase in mRNA levels of the hippocampal mineralocorticoid receptor (MR, type I) that is thought to play an important role in mediating the negative feedback effects of low levels of steroids on the hypothalamic-pituitary-adrenal (HPA) axis. Imipramine also decreased proopiomelanocortin (POMC) mRNA levels by 38% and glucocorticoid receptor (GR, type II) mRNA levels by 51% in the anterior pituitary. With the exception of a 20% decrease in TH mRNA in the LC after 2 wk of imipramine administration, none of these changes in gene expression were evident as a consequence of short-term administration of the drug. In the light of data that major depression is associated with an activation of brain CRH and LC-NE systems, the time-dependent effect of long-term imipramine administration on decreasing the gene expression of CRH in the hypothalamus and TH in the LC may be relevant to the therapeutic efficacy of this agent in depression.
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PMID:Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications. 167 67

Literature on case reports, clinical studies and biochemical mechanisms of the sweet-tasting compound glycyrrhizic acid in liquorice was critically reviewed to provide a safety assessment of its presence in liquorice sweets. A high intake of liquorice can cause hypermineralocorticoidism with sodium retention and potassium loss, oedema, increased blood pressure and depression of the renin-angiotensin-aldosterone system. As a consequence, a number of other clinical symptoms have also been observed. Glycyrrhizic acid is hydrolysed in the intestine to the pharmacologically active compound glycyrrhetic acid, which inhibits the enzyme 11 beta-hydroxysteroid dehydrogenase (in the direction of cortisol to cortisone) as well as some other enzymes involved in the metabolism of corticosteroids. Inhibition of 11 beta-hydroxysteroid dehydrogenase leads to increased cortisol levels in the kidneys and in other mineralocorticoid-selective tissues. Since cortisol, which occurs in much larger amounts than aldosterone, binds with the same affinity as aldosterone to the mineralocorticoid receptor, the result is a hypermineralocorticoid effect of cortisol. The inhibitory effect on 11 beta-hydroxysteroid dehydrogenase is reversible; however, the compensatory physiological mechanisms following hypermineralocorticoidism (e.g. depression of the renin-angiotensin system) may last several months. It is not possible, on the basis of existing data, to determine precisely the minimum level of glycyrrhizic acid required to produce the described symptoms. There is apparently a great individual variation in the susceptibility to glycyrrhizic acid. In the most sensitive individuals a regular daily intake of no more than about 100 mg glycyrrhizic acid, which corresponds to 50 g liquorice sweets (assuming a content of 0.2% glycyrrhizic acid), seems to be enough to produce adverse effects. Most individuals who consume 400 mg glycyrrhizic acid daily experience adverse effects. Considering that a regular intake of 100 mg glycyrrhizic acid/day is the lowest-observed-adverse-effect level and using a safety factor of 10, a daily intake of 10 mg glycyrrhizic acid would represent a safe dose for most healthy adults. A daily intake of 1-10 mg glycyrrhizic acid/person has been estimated for several countries. However, an uneven consumption pattern suggests that a considerable number of individuals who consume large amounts of liquorice sweets are exposed to the risk of developing adverse effects.
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PMID:Glycyrrhizic acid in liquorice--evaluation of health hazard. 838 90

The effects of chronic stress on the hypothalamic-pituaitary-adrenocortical (HPA) axis were studied in five inbred rat strains, i.e. Brown Norway (BN), Fischer (FIS), Lewis (LEW), Spontaneously Hypertensive (SHR) and Wistar Kyoto (WKY). Previously, these rat strains had been shown to display clear behavioral differences in the forced swimming test that presumably measures depression-like behavior, BN and WKY being more passive than the other strains. Here we test the hypothesis that the differences in behavioral immobility might be associated with an abnormal HPA response to chronic immobilization (IMO) stress. In stressnaive rats under basal conditions (morning) there were no differences among strains in adrenal weight, serum adrenocorticotropin hormone (ACTH) and corticosterone (B) levels, cortictropin-releasing factor (CRF) mRNA in the hypothalamic paraventricular nucleus (PVN) and hippocampal glucocorticoid and mineralocorticoid receptor (GR and MR) mRNA. After chronic IMO, basal serum ACTH levels were increased in LEW, SHR and WKY, but not in BN or FIS rats, whereas basal B levels were increased in BN, FIS, SHR and WKY rats, but not in LEW. The increase in adrenal weight was also strain dependent and correlated negatively with chronic IMO-induced hypercorticosteronemia. These peripheral differences among strains were not observed at central levels. Thus, chronic IMO increased the CRF mRNA content in the PVN, analyzed by in situ hybridization, similarly in all strains. In addition, after chronic IMO no differences were found among strains in hippocampal GR mRNA and RM mRNA contents. Considering data from all strains together, chronic IMO reduced the GR mRNA (50-60%) content in the hippocampal CA1, CA3 and DG areas, and slightly diminished (11-13%) MR mRNA levels in CA1 and CA3 areas. The present results indicate that: (i) chronic IMO down-regulates GR mRNA in the hippocampus and slightly up-regulates CRF mRNA in the hypothalamic PVN similarly in all strains; (ii) after chronic IMO interstrain differences were observed in serum ACTH and B levels as well as adrenal hypertrophy; (iii) some changes are probably located at the adrenal level since changes in serum B level and adrenal weight were not related to changes in ACTH; (iv) in LEW and WKY rats, B hyporesponsiveness to chronic IMO might be linked to low adrenal sensitivity to ACTH, and (v) HPA axis changes induced by the chronic IMO procedure are not related to previously reported data on depressive-like behavior of BN and WKY in the forced swimming test.
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PMID:Hypothalamic-pituitary-adrenal response to chronic stress in five inbred rat strains: differential responses are mainly located at the adrenocortical level. 873 88

Abnormal interactions between serotonin (5-hydroxytryptamine) and glucocorticoids, notably in the hippocampus, may underpin neuroendocrine, affective and cognitive dysfunction in depression and ageing. Glucocorticoids act via intracellular glucocorticoid and mineralocorticoid receptors, whereas 5-hydroxytryptamine binds to a family of transmembrane sites; both cross- and auto-regulation have been proposed. To determine the roles of 5-hydroxytryptamine and corticosterone in the short-term control of hippocampal receptor gene expression, we used 3,4-methylenedioxymethamphetamine (20 mg/kg), which causes acute release of both 5-hydroxytryptamine and corticosterone. 3,4-methylenedioxymethamphetamine increased mineralocorticoid receptor messenger RNA expression throughout the hippocampus after 16 h. In rats with fixed glucocorticoid levels (adrenalectomy plus corticosterone pellets) this effect was lost in CA1-4, suggesting corticosterone-mediation, but maintained in the dentate gyrus, indicating 5-hydroxytryptamine involvement. In contrast, 3,4-methylenedioxymethamphetamine decreased glucocorticoid receptor messenger RNA expression in the dentate gyrus and CA1 within 4 h, but only in adrenal-intact rats, suggesting corticosterone control. 5-Hydroxytryptamine1A receptor messenger RNA expression was decreased in CA1 in both groups of rats, but increased in the dentate gyrus only in corticosterone-fixed rats, suggesting 5-hydroxytryptamine differentially regulates expression of this gene within hippocampal subfields. 5-hydroxytryptamine2C receptor messenger RNA was decreased in ventral CA1 only in adrenal-intact rats, suggesting a corticosterone effect, and decreased in the subiculum in both groups, indicating 5-hydroxytryptamine mediation. These results show the complexity and intricate subregional-specificity of 5-hydroxytryptamine and corticosterone interactions upon hippocampal corticosteroid and 5-hydroxytryptamine receptor gene expression. 3,4-Methylenedioxymethamphetamine-induced alterations in hippocampal receptor gene expression may play a role in the mood and behavioural changes associated with this drug of abuse.
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PMID:Site-specific regulation of corticosteroid and serotonin receptor subtype gene expression in the rat hippocampus following 3,4-methylenedioxymethamphetamine: role of corticosterone and serotonin. 913 93

Both serotonergic dysfunction and glucocorticoid hypersecretion are implicated in affective and eating disorders. The adverse effects of serotonergic (5-HT)2C receptor activation on mood and food intake, the antidepressant efficacy of 5-HT2 receptor antagonists, and the hyperphagia observed in 5-HT2C receptor knockout mice all suggest a key role for increased 5-HT2C receptor-mediated neurotransmission. Glucocorticoids, however, downregulate 5-HT2C receptor mRNA in the hippocampus, and it is unclear how increased 5-HT2C receptor sensitivity is achieved in the presence of elevated glucocorticoid levels in depression. Here we show a monophasic diurnal rhythm of 5-HT2C receptor mRNA expression in the rat hippocampus that parallels time-dependent variations in 5-HT2C receptor agonist-induced behaviors in open field tests. Rats entrained to chronic food restriction show marked but intermittent corticosterone hypersecretion and maintain an unaltered 5-HT2C receptor mRNA rhythm. The 5-HT2C receptor mRNA rhythm, however, is suppressed by even modest constant elevations of corticosterone (adrenalectomy + pellet) or with elevated corticosterone during the daytime (8 A.M.), whereas a normal rhythm exists in animals that have the same dose of corticosterone in the evening (6 P.M.). Thus, animals showing even a transient daytime corticosterone nadir exhibit normal hippocampal 5-HT2C receptor mRNA rhythms, even in the presence of overt corticosterone hypersecretion. Chronic food restriction also abolishes the normal diurnal variation in hippocampal glucocorticoid receptor (GR) and mineralocorticoid receptor mRNAs and produces, unusually, both elevated corticosterone and increased GR. The mismatch between elevated glucocorticoids and maintained 5-HT2C receptor and increased GR gene expression in the hippocampus provides a new model to dissect mechanisms that may underlie affective and eating disorders.
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PMID:Dysregulation of diurnal rhythms of serotonin 5-HT2C and corticosteroid receptor gene expression in the hippocampus with food restriction and glucocorticoids. 915 22

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 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

Recent studies indicated that hyperactivity of the hypothalamo-pituitary-adrenal system is a considerable risk factor for the precipitation of affective disorders, most notably of major depression. The mechanism by which this hyperactivity eventually leads to clinical symptoms of depression is unknown. In the present animal study, we tested one possible mechanism, i.e., that long-term exposure to high corticosterone levels alters functional responses to serotonin in the hippocampus, an important area in the etiology of depression. Rats were injected daily for 3 weeks with a high dose of corticosterone; electrophysiological responses to serotonin were recorded intracellularly from CA1 pyramidal neurons in vitro. We observed that daily injections with corticosterone gradually attenuate the membrane hyperpolarization and resistance decrease mediated by serotonin-1A receptors. We next used single-cell antisense RNA amplification from identified CA1 pyramidal neurons to resolve whether the functional deficits in serotonin responsiveness are accompanied by decreased expression levels of the serotonin-1A receptor. It appeared that expression of serotonin-1A receptors in CA1 pyramidal cells is not altered; this result was supported by in situ hybridization. Expression of corticosteroid receptors in the same cells, particularly of the high-affinity mineralocorticoid receptor, was significantly reduced after long-term corticosterone treatment. The present findings indicate that prolonged elevation of the corticosteroid concentration, a possible causal factor for major depression in humans, gradually attenuates responsiveness to serotonin without necessarily decreasing serotonin-1A receptor mRNA levels in pyramidal neurons. These functional changes may occur by a posttranscriptional mechanism or by transcriptional regulation of genes other than the serotonin-1A receptor gene itself.
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PMID:Long-term exposure to high corticosterone levels attenuates serotonin responses in rat hippocampal CA1 neurons. 1055 42


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