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)

Evidence suggests that individuals with posttraumatic stress disorder (PTSD) have enhanced sensitization of the hypothalamic-pituitary-adrenocortical (HPA) axis. Fourteen adolescent inpatients with DSM-IV PTSD were compared with 14 adolescent hospitalized controls without current axis I diagnoses. All patients were drug-naive. The causative trauma had been sexual abuse in all cases. Dexamethasone, 1 mg orally, was given at 11 PM, 5 days after admission. Baseline blood samples were obtained at 8 AM, and on the following day, adrenocorticotropin (ACTH) and cortisol levels were measured at 8 AM, 4 PM, and 11 PM. Clinical assessment included the Impact of Event Scale, Stanford Acute Stress Reaction Questionnaire, Beck Depression Inventory, and Coping Inventory for Stressful Situations. Post-DST ACTH levels were significantly lower in PTSD than in control adolescents (at 8 AM, P <0.005; at 4 PM, P <0.001; and at 11 PM, P <0.05). In patients, post-DST cortisol levels were reduced but not significantly. No correlations were found between ACTH and cortisol levels and time elapsed since trauma. These results demonstrate that sexually abused adolescents with PTSD show ACTH hypersuppression to DST, suggesting enhanced glucocorticoid receptor sensitivity in the pituitary.
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PMID:Increased adrenocorticotropin suppression after dexamethasone administration in sexually abused adolescents with posttraumatic stress disorder. 1567 26

The hypothalamic-pituitary-adrenal (HPA) axis plays important roles in maintaining alertness and modulating sleep. Dysfunction of this axis at any level (CRH receptor, glucocorticoid receptor, or mineralocorticoid receptor) can disrupt sleep. Herein, we review normal sleep, normal HPA axis physiology and circadian rhythm, the effects of the HPA axis on sleep, as well as the effects of sleep on the HPA axis. We also discuss the potential role of CRH in circadian-dependent alerting, aside from its role in the stress response. Two clinically relevant sleep disorders with likely HPA axis dysfunction, insomnia and obstructive sleep apnea, are discussed. In insomnia, we discuss how HPA axis hyperactivity may be partially causal to the clinical syndrome. In obstructive sleep apnea, we discuss how HPA axis hyperactivity may be a consequence of the disorder and contribute to secondary pathology such as insulin resistance, hypertension, depression, and insomnia. Mechanisms by which cortisol can affect slow wave sleep are discussed, as is the role the HPA axis plays in secondary effects of primary sleep disorders.
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PMID:On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep: normal HPA axis activity and circadian rhythm, exemplary sleep disorders. 1572 14

Behavioral stress has been shown to enhance long-term depression (LTD) in the CA1 region of the hippocampus, but the underlying mechanisms remain unclear. In the present study, we found that selectively blocking NR2B-containing NMDA receptors (NMDARs) abolishes the induction of LTD by prolonged low-frequency stimulation (LFS) in slices from stressed animals. Additionally, there is no need to activate NR2A-containing or synaptic NMDARs to induce this LTD, suggesting that LTD observed in slices from stressed animals is triggered primarily by extrasynaptic NMDAR activation. In contrast, stress has no effect on LTD induced by either a brief bath application of NMDA or a combination of LFS with the glutamate-uptake inhibitor DL-threo-beta-benzyloxyaspartate (DL-TBOA). Furthermore, saturation of LFS-induced LTD in slices from stressed animals occludes the subsequent induction of LTD by LFS in the presence of dl-TBOA. We also found that stress induces a profound decrease in the glutamate uptake in the synaptosomal fraction of the hippocampal CA1 region. These effects were prevented when the animals were given a glucocorticoid receptor antagonist, 11beta,17beta-11[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-(propynyl)-estra-4,9-dien-3-one, before experiencing stress. These results suggest that the blockade of glutamate uptake is a potential mechanism underlying the stress-induced enhancement of LTD and point to a novel role for glutamate-uptake machinery in the regulation of synaptic plasticity induction.
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PMID:Behavioral stress enhances hippocampal CA1 long-term depression through the blockade of the glutamate uptake. 1585 55

Our interest in nuclear receptors (NRs) originated from early studies on hepatic steroid metabolism. We discovered a new hypothalamo-pituitary-liver axis, imprinted neonatally by androgens and operating through sexually differentiated GH secretory patterns. Male and female patterns have opposite effects on sexually differentiated hepatic genes, explaining sexually dimorphic liver patterns. To further understand steroid action, we purified the glucocorticoid receptor (GR) leading to our discovery of the NR three-domain structure, with separable DNA binding domain and ligand binding domains and a third domain now known to have transcriptional regulatory properties. Knowledge of this domain structure has been immensely important for deciphering NR actions. Using this first purified NR, we collaborated with Keith Yamamoto and first demonstrated specific NR binding to DNA. This also was the first demonstration of a mammalian transcription factor, a breakthrough that led to discovery of NR response elements. In further collaboration with Yamamoto, we cloned the first NR cDNA sequences, leading to cloning of the superfamily of NR genes. With Yamamoto and Kaptein, we determined the first three-dimensional NR structure, that of DNA binding domain. Later work on orphan receptors resulted in the first discovery of: 1) endogenous ligands for an orphan receptor (fatty acids as activators of peroxisomal proliferator-activated receptor alpha); 2) liver X receptor beta (OR-1) and its role in central nervous system cholesterol homeostasis; and 3) estrogen receptor beta, leading to a paradigm shift in understanding of estrogen signaling, of importance in endocrinology, immunology, and oncology and to development of estrogen receptor beta agonists for treatment of autoimmune diseases, prostate disease, depression, and ovulatory dysfunction.
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PMID:Steroids and the scientist. 1591 10

Children prenatally exposed to alcohol typically exhibit behavioral abnormalities, including hyperactivity, learning deficits, and an increased prevalence of depression. Similar impairments are found in children of hypothyroid mothers, and we have shown that alcohol-consuming rat dams have suppressed hypothalamic-pituitary-thyroid (HPT) function. Therefore, we hypothesized that suppressed maternal thyroid hormonal milieu may contribute to the deleterious consequences of prenatal alcohol exposure. We aimed first to confirm and then to reverse the behavioral deficits in the fetal alcohol exposed (FAE) rat offspring by administration of thyroxine (T4) to the alcohol-consuming dams. Adult offspring prenatally exposed to ethanol (FAE; 35% ethanol-derived calories), pair-fed (PF) or control (C) diets were tested in the Morris water maze (MWM), the forced swim test (FST), and the open field test (OFT) to assess spatial learning, depressive behavior, and exploratory behavior/anxiety, respectively. Adult FAE offspring took longer to locate a hidden platform in the MWM and showed increased depressive behavior in the FST both of which were reversed by administration of T4 to the alcohol-consuming mother. We found sex and brain region-specific alterations in expression of genes involved in these behaviors in FAE adult offspring. Specifically, decreased hippocampal GAP-43 mRNA levels in adult FAE females and decreased glucocorticoid receptor (GR) expression in the amygdala of male and female FAE offspring were observed. The decreased mRNA levels of GAP-43 and GR were normalized by T4 treatment to the alcohol-consuming mother. Our results suggest that the suppressed HPT function of the alcohol-consuming mother contributes to the behavioral and cognitive dysfunctions observed in the offspring.
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PMID:Behavioral deficits associated with fetal alcohol exposure are reversed by prenatal thyroid hormone treatment: a role for maternal thyroid hormone deficiency in FAE. 1594 Feb 94

Altered glucocorticoid receptor (GR) signaling is a postulated mechanism for the pathogenesis of major depression. To mimic the human situation of altered GR function claimed for depression, we generated mouse strains that underexpress or overexpress GR, but maintain the regulatory genetic context controlling the GR gene. To achieve this goal, we used the following: (1) GR-heterozygous mutant mice (GR+/-) with a 50% GR gene dose reduction, and (2) mice overexpressing GR by a yeast artificial chromosome resulting in a twofold gene dose elevation. GR+/- mice exhibit normal baseline behaviors but demonstrate increased helplessness after stress exposure, a behavioral correlate of depression in mice. Similar to depressed patients, GR+/- mice have a disinhibited hypothalamic-pituitary-adrenal (HPA) system and a pathological dexamethasone/corticotropin-releasing hormone test. Thus, they represent a murine depression model with good face and construct validity. Overexpression of GR in mice evokes reduced helplessness after stress exposure, and an enhanced HPA system feedback regulation. Therefore, they may represent a model for a stress-resistant strain. These mouse models can now be used to study biological changes underlying the pathogenesis of depressive disorders. As a first potential molecular correlate for such changes, we identified a downregulation of BDNF protein content in the hippocampus of GR+/- mice, which is in agreement with the so-called neurotrophin hypothesis of depression.
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PMID:Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions. 1598 54

The aim of this study was to evaluate the efficacy of agomelatine (S 20098) to accelerate reversal of the neuroendocrinological, behavioural and cyclical changes seen in a transgenic mouse model of the neuroendocrine characteristics of depression. The effects of agomelatine were assessed in transgenic mice with low glucocorticoid receptor (GR) function, after acute stress or induced phase shift, and compared to desipramine and melatonin. Mice were injected 2 h before the onset of the dark period with agomelatine (10 mg/kg, i.p.), desipramine (10 mg/kg, i.p.), melatonin (10 mg/kg, i.p.) or vehicle (hydroxy-ethyl-cellulose (HEC) 1%) each day for 21 to 42 days. Agomelatine was effective in reversing the transgenic mouse behavioural changes noted in the Porsolt forced swim test as well as in the elevated plus maze. Both the number of open arm entries and the total time spent in open arms of the elevated plus maze is greatly increased in transgenic mice. The mean time spent in open arms is exquisitely sensitive to reversal by agomelatine and desipramine. Agomelatine also markedly accelerated readjustment of circadian cycles of temperature and activity following an induced phase shift. This action of agomelatine was superior to that of melatonin while desipramine was without effect. The accelerating effect of agomelatine was particularly notable if treatment was started 3 weeks prior to the induced phase shift. Agomelatine treatment did not cause any major change in corticosterone or adrenocorticotropic hormone (ACTH) concentrations nor in vasopressin (AVP), corticotropin-releasing hormone (CRH), GR and mineralocorticoid receptor (MR) mRNAs levels, which make it unlikely that the mechanism of agomelatine action is related to hypothalamic-pituitary-adrenocortical (HPA) axis changes. The present study shows that agomelatine displays some characteristics of antidepressant drug action in the transgenic mouse model, effects that could be partially related to its chronobiotic properties.
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PMID:Antidepressant action of agomelatine (S 20098) in a transgenic mouse model. 1600 35

The forced swim test (FST) can lead to stress-related diseases such as depression, through activation of hypothalamic-pituitary-adrenal axis (HPAA) and corticosteroid disregulation. Among the proopiomelanocortin (POMC)-derived peptides, alpha-melanocyte-stimulating hormone (alpha-MSH) has been shown to regulate long-lasting behavioral responses. Moreover, serotonergic pathways in various brain areas are activated by stressors, a feature that suggests a role for serotonin in both stress-induced HPAA disregulation and depressive physiopathology. Taking all together these data, we investigated the effects of the FST exposure and the effects of pre-treatment with alpha-MSH on cortical synaptosomal serotonin transporter (SERT) activity, corticosterone (CORT) plasma levels and on glucocorticoid receptor (GR) occupancy and expression in rat hippocampus. Young male rats were divided into three groups treated with saline or with alpha-MSH at doses of 1 or 4 microg/rat, 15 min prior to FST. Our data show that FST increased CORT secretion; GR levels in hippocampus decreased in density after stress without variations in affinity; GR redistributed from the cytosolic to the nuclear tissue fraction; finally, SERT activity strongly increased. All these effects were blocked by pre-treatment with alpha-MSH at the higher dose.
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PMID:Effects of swim stress and alpha-MSH acute pre-treatment on brain 5-HT transporter and corticosterone receptor. 1602 86

It has been hypothesized that pro-inflammatory response and hyperactivity of hypothalamic-pituitary-adrenocortical axis (HPA) are involved in the pathogenesis of depression. Hyperactivity of HPA axis results probably from deregulation of glucocorticoid receptor function and impairment of the control mechanism of glucocorticoid secretion. Previously, we found that antidepressants inhibited glucocorticoid receptor (GR) function under the in vitro condition. In order to study a role of some mediators of pro-inflammatory response in this process, presently, we investigated the effect of lipopolysaccharide (LPS) on imipramine- or fluoxetine-induced inhibition of GR-mediated gene transcription in fibroblast cells, stably transfected with mouse mammary tumor virus promoter (LMCAT cells). Two days of incubation of the cells with imipramine (3-10 microM), fluoxetine (10 microM) or LPS (1 microg/ml) inhibited the corticosterone-induced gene transcription. Concomitant incubation of the cells with LPS and fluoxetine or imipramine had stronger inhibitory effect than that evoked by each compound alone. Moreover, we found that fluoxetine (10 microM) but not imipramine (3-10 microM) significantly inhibited the LPS-stimulated interleukin-6 (IL-6) production in these cells. These data suggest that pro-inflammatory agents facilitate antidepressant-induced inhibition of glucocorticoid receptor function.
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PMID:Effect of lipopolysaccharide and antidepressant drugs on glucocorticoid receptor-mediated gene transcription. 1612 23

Regulation of neurotransmission via group-III metabotropic glutamate receptors (mGluR4, -6, -7, and -8) has recently been implicated in the pathophysiology of affective disorders, such as major depression and anxiety. For instance, mice with a targeted deletion of the gene for mGluR7 (mGluR7-/-) showed antidepressant and anxiolytic-like effects in a variety of stress-related paradigms, including the forced swim stress and the stress-induced hyperthermia tests. Deletion of mGluR7 reduces also amygdala- and hippocampus-dependent conditioned fear and aversion responses. Since the hypothalamic-pituitary-adrenal (HPA) axis regulates the stress response we investigate whether parameters of the HPA axis at the levels of selected mRNA transcripts and endocrine hormones are altered in mGluR7-deficient mice. Over all, mGluR7-/- mice showed only moderately lower serum levels of corticosterone and ACTH compared with mGluR7+/+ mice. More strikingly however, we found strong evidence for upregulated glucocorticoid receptor (GR)-dependent feedback suppression of the HPA axis in mice with mGluR7 deficiency: (i) mRNA transcripts of GR were significantly upregulated in the hippocampus of mGluR7-/- animals, (ii) similar increases were seen with 5-HT1A receptor transcripts, which are thought to be directly controlled by the transcription factor GR and finally (iii) mGluR7-/- mice showed elevated sensitivity to dexamethasone-induced suppression of serum corticosterone when compared with mGluR7+/+ animals. These results indicate that mGluR7 deficiency causes dysregulation of HPA axis parameters, which may account, at least in part, for the phenotype of mGluR7-/- mice in animal models for anxiety and depression. In addition, we present evidence that protein levels of brain-derived neurotrophic factor are also elevated in the hippocampus of mGluR7-/- mice, which we discuss in the context of the antidepressant-like phenotype found in those animals. We conclude that genetic ablation of mGluR7 in mice interferes at multiple sites in the neuronal circuitry and molecular pathways implicated in affective disorders.
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PMID:Metabotropic glutamate receptor subtype 7 ablation causes dysregulation of the HPA axis and increases hippocampal BDNF protein levels: implications for stress-related psychiatric disorders. 1623 91


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