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)

Since the discovery of CRH in 1981, several investigators have reported abnormalities of the hypothalamic-pituitary-adrenal (HPA) system in response to direct stimulation of the corticotroph cells in patients with psychiatric disorders. To further explore HPA system integrity in major depressive disorders, 13 drug-free patients and normal subjects matched for age, sex, ovarian status, and body weight received 100 micrograms synthetic human CRH as an iv bolus dose. Compared to that in the normal subjects, in the depressed patients a significant attenuation of the net ACTH release after CRH administration (772 +/- 597 vs. 263 +/- 286 pmol/min.L; P less than 0.02) was observed, while beta-endorphin and cortisol responses did not differ significantly between the groups. The magnitudes of ACTH and cortisol release were negatively correlated in the patient group only (r = -0.67; P less than 0.01). Thus, the blunted ACTH response to CRH in depression might be related to hypercortisolemia, while the implications of the apparent dissociation of ACTH and beta-endorphin after CRH administration still remain unclear. Our data support the hypothesis that the hyperactivity of the HPA system in depression most likely is a consequence of CRH hypersecretion, the origin of which may be explained by abnormal central glucocorticoid receptor or neurotransmitter regulation.
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PMID:Blunted adrenocorticotropin but normal beta-endorphin release after human corticotropin-releasing hormone administration in depression. 254 28

Current theories of affective disorders do not account for many of the biological markers replicated in patient studies. We link many biological findings in a reasonable physiological relationship, compatible with mechanisms of action of pharmacological and electroshock therapies for depression. We propose that excessive phospholipase-A2 (PLA2) activity disrupts membrane fluidity, composition, and therefore, the activity, of membrane-dependent proteins. Similar disruptions in these proteins are documented in depressed patients and can be accounted for by excessive PLA2 activity. This paradigm accounts for disturbances in the activity of Na-K-ATPase, beta2- and alpha2-adrenergic receptors, MAO, norepinephrine and serotonin uptake, and imipramine binding. Disturbances in other membrane-dependent proteins, tyrosine and tryptophan hydroxylase, can explain the biogenic amine hypothesis. Inhibition of glucocorticoid receptor and TRH receptor binding to their respective ligands by PLA2 may explain patient nonsuppression in the Dexamethasone Suppression Test and poor response in the TRH stimulation test. Physiological regulators of PLA2 activity; calcium, cortisol, estrogen, progesterone, and PGE2 are documented abnormalities in some patients with affective disorders and consistent with excessive PLA2 activity. Thus, postpartum depression and premenstrual tension syndrome may be described in the paradigm. The mechanisms of action of tricyclic antidepressants, lithium, electroconvulsive shock, and some novel antimanic agents can be described in terms of alterations of PLA2 activity. Interestingly, ethanol perturbs membrane fluidity and membrane-bound enzymes in a manner similar to excessive PLA2 activity. A hereditary factor predisposing patients to affective disorders may be a gene defect at either PLA2 or in its regulation.
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PMID:Are disturbances in lipid-protein interactions by phospholipase-A2 a predisposing factor in affective illness? 256 35

Circulating lymphocytes are frequently used to study glucocorticoid receptor (GR) regulation in various clinical disease states, such as depression. Since little is known about the relationship between lymphoid and neuronal GR, type II adrenal steroid receptors (i.e., GR) were quantitated in neuronal (hippocampus, frontal cortex, hypothalamus), lymphoid (circulating lymphocytes, spleen, thymus) as well as pituitary tissues of adrenal-intact and 1 day adrenalectomized (ADX) rats using the selective type II receptor ligand, [3H]RU 28362. Specific, high affinity (dissociation constant = 0.2-0.3 nM) type II receptors were present in all tissues examined with the density in 1 day ADX rats being thymus greater than frontal cortex = spleen greater than hippocampus = pituitary greater than hypothalamus greater than lymphocytes. Adrenal intact rats had fewer type II receptors in frontal cortex, hippocampus and spleen as compared to 1 day ADX rats. Dose-response competition studies using [3H]RU 28362 and various unlabelled steroids revealed a binding profile indicative of a type II receptor with the potency being RU 28362 greater than triamcinolone acetonide greater than dexamethasone = corticosterone much greater than aldosterone in both whole brain and spleen soluble fractions. In contrast to the high concentration of type II receptors in the various tissues, the density of type I (i.e., mineralocorticoid) receptors was very low or nondetectable in the same tissues of 1 day ADX rats with the notable exception of the hippocampus where there were approximately comparable levels of both receptors. These results document the widespread distribution of type II adrenal steroid receptors in neuronal and lymphoid tissues which are similar in affinity and steroid specificity.
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PMID:Quantification of type I and II adrenal steroid receptors in neuronal, lymphoid and pituitary tissues. 260 14

1. The 41 amino acid peptide human corticotropin releasing hormone (h-CRH) and its ovine analogue o-CRH are regulators of proopiomelanocortin (POMC) derived neuropeptides and neurosteroids of the limbic-hypothalamic-pituitary-adrenocortical (LHPA) axis such as beta-endorphin, corticotropin (ACTH) and corticosteroids modulating concomitantly hormonal and behavioral systems in animal and man, e.g. adaptation to stress. 2. Challenge tests employing h-CRH stimulation with or without different kinds of pretreatment in affective disorders, alcoholism, and panic disorder demonstrate LHPA alterations that are induced by dysregulations in the limbic area. In depression, the enhanced secretory activity of pituitary corticotrophs or altered feedback regulation is compatible with endogenous CRH hypersecretion followed by enhanced production of proopiomelanocortin whose fragments activate synthesis and release of adrenal corticosteroids. These effects are accompanied by development of a functional hyperplasia of the adrenocortex and/or down-regulation of pituitary CRH-receptors and/or reduced negative feed back capacity of limbic glucocorticoid receptor containing neurones particularly in the hippocampus. Similar disturbances are found in hypercortisolemic patients withdrawn from alcohol and are less pronounced in patients with panic disorder. 3. Repetitive h-CRH administration to normal controls induces sleep-EEG and neuroendocrine effects resembling those in depression. 4. Adrenocortical hormones act back on neurotransmitter/receptor sites of brain systems relevant for neuropharmacoloy (e.g. GABA receptor activity in anxiety disorders and affective disorders). 5. The neuroendocrine approach to the LHPA axis is of value to uncover several aspects of pathology underlying various psychiatric diseases.
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PMID:Human corticotropin releasing hormone: clinical studies in patients with affective disorders, alcoholism, panic disorder and in normal controls. 285 97

The effect of in vivo (1 mg) and in vitro (10(-7)-10(-10) M) dexamethasone administration on mitogen-induced lymphocyte proliferation was examined in drug-free depressed patients, nondepressed psychiatric patients, as well as normal controls, and was related to the results of a standard overnight Dexamethasone Suppression Test (DST). The effect of oral dexamethasone administration was also examined for its effect on lymphocyte cytosolic glucocorticoid receptor content. Oral dexamethasone administration significantly decreased both phytohemagglutinin (PHA) and concanavalin A (Con-A) induced lymphocyte proliferation, as well as glucocorticoid receptor number in suppressors, whereas dexamethasone failed to decrease these responses in nonsuppressors. Nonsuppressors had significantly lower serum dexamethasone levels compared to suppressors at both 8:00 AM and 4:00 PM. However, when differences in serum dexamethasone levels were covaried out, there were still significant differences between suppressors and nonsuppressors on the dexamethasone-induced mitogen changes, but the changes in glucocorticoid receptor content were no longer significant. In vitro incubation of lymphocytes with dexamethasone produced a dose-related decrease in mitogenesis, which was not different between the depressed and nondepressed groups. However, at physiologically relevant concentrations of dexamethasone (10(-9)-10(-10) M), nonsuppressors as compared to suppressors were more resistant to the immunosuppressive effects of in vitro dexamethasone on the Con-A response. The inhibitory effect of in vitro dexamethasone on Con-A-stimulated lymphocytes was positively correlated with basal 4:00 PM cortisol values. In conclusion, in vitro techniques are useful probes to assess glucocorticoid sensitivity in depression. The present results also further support the hypothesis that glucocorticoid insensitivity is associated with DST nonsuppression.
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PMID:Comparison of in vivo and in vitro glucocorticoid sensitivity in depression: relationship to the dexamethasone suppression test. 326 79

The correlation between the level of stress-induced natural killer (NK) depression and glucocorticoid binding to specific spleen cell receptors and hormonal profile in inbred mouse strains (CBA, BALB/c, C57BL/c, A/Sn) has been investigated. Stable interstrain differences in stress-induced natural killer activity and glucocorticoid receptor binding (Bm and Kd) have been revealed. It was demonstrated that the mechanism of NK activity depression during stress consists in genetically determined potential sensitivity of lymphoid cells to physiological fluctuations of glucocorticoid levels. This made it possible to identify stress-resistant and stress-sensitive mouse strains.
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PMID:[Interstrain differences in cellular glucocorticoid reception in mice and the degree of suppression of normal killer activity during immobilization stress]. 382 99

Desipramine (DMI), a tricyclic antidepressant drug used in the treatment of depression, has been shown to increase steady-state levels of glucocorticoid receptor type II (GRII) mRNA in vitro and in vivo. To determine whether this effect is secondary to norepinephrine (NE) reuptake inhibition i.e., increases in synaptic NE induced by DMI, GRII mRNA levels were assayed in rat hippocampus following neurotoxic lesioning of NE neurons with DSP4. Chronic DMI treatment significantly increased GRII mRNA levels to the same degree in lesioned and non-lesioned animals. In contrast to DMI, the non-tricyclic antidepressant fluoxetine had no effect on GRII mRNA. These results provide evidence which demonstrates that a tricyclic antidepressant can regulate steady-state mRNA levels in vivo by a mechanism which is independent of its effects on synaptic monoamine levels.
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PMID:Norepinephrine-independent regulation of GRII mRNA in vivo by a tricyclic antidepressant. 758 16

Alterations in the hypothalamic-pituitary-adrenal (HPA) system are well documented in affective disorders. In depression these include increased secretion of cortisol, an insufficient suppressibility of cortisol by dexamethasone, a blunted corticotropin (ACTH) response to corticotropin-releasing hormone (CRH) and a dysfunction of the glucocorticoid receptor. Patients with atopic eczema, a common chronic skin disease, show seasonal variations in disease activity, symptoms of minor depression and immunological disturbances similar to those seen in patients with depression. To explore the integrity of the HPA system integrity in individuals with atopic eczema we studied the 24-h cortisol secretion and the cortisol, ACTH and beta-endorphin responses to CRH in such individuals and in healthy controls matched for sex and age. The 24-h secretion of cortisol did not differ between the patients with atopic eczema and the controls. The net response to CRH administered as a 100 micrograms i.v. bolus was significantly attenuated for both cortisol (24,235 +/- 12,443 vs. 47,019 +/- 34,515 nmol.min/dl; p < .03) and for ACTH (546 +/- 205 vs. 727 +/- 310 pmol.min/l; p < .05) in the patient group, whereas the beta-endorphin response did not differ between the groups (1072 +/- 448 vs. 1603 +/- 421 nmol.min/l). The blunted response of cortisol and ACTH cannot be explained by hypercortisolism as it is the case in major depression. Rather, it may be related to a prolonged underexposure to hypothalamic CRH or to an increased sensitivity of glucocorticoid feedback inhibition.
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PMID:Cortisol, corticotropin, and beta-endorphin responses to corticotropin-releasing hormone in patients with atopic eczema. 767 38

1. The topical distribution of tritiated dexamethasone (DEX), a potent synthetic glucocorticoid of widespread use in the diagnosis and assessment of mental illness, was studied in rat CNS by autoradiography to obtain information on potential target sites for feedback and other centrally mediated effects of glucocorticoids. 2. The cells of the arcuate nucleus of the hypothalamus and the lateral thalamic nuclei displayed the most concentrated nuclear accumulation of silver grains. 3. Significant accumulation, exceeding that found in the hippocampal formation, also occurred in the cells of the ventromedial, periventricular, and paraventricular nuclei of the hypothalamus, the locus ceruleus, the nucleus tractus solitarii, and the area postrema, none of which are targeted by corticosterone, the native glucocorticoid of the rat. 4. Nuclear accumulation of silver grains was prominent in neural and glial cells of the cerebral cortex, the olfactory nucleus, the dorsolateral septum, the amygdala, the subfornical organ, the lateral parabrachial, medial trapezoid, and dorsal reticular nuclei, the nucleus centralis of the raphe, the cerebellum, and vascular tissues. 5. The localization of DEX in hypothalamic and brain-stem nuclei coincided with that of the glucocorticoid receptor, possibly implicating these sites in direct or modulating effects of glucocorticoids in various forms of mental disturbance, including depression, anxiety, panic disorders, and alcohol withdrawal. 6. The extent to which various CNS regions targeted by DEX feature in negative feedback control of adrenocortical secretion remains to be defined, as does the site of impaired feedback disclosed by the dexamethasone suppression test in psychiatric patients.
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PMID:Dexamethasone target sites in the central nervous system and their potential relevance to mental illness. 825 8

Increased glucocorticoid secretion is frequent in mood disorders and is normalized by long-term antidepressant therapy. Many antidepressants act by increasing central serotonin transmission. We investigated the effects of a serotonin precursor, indole-pyruvic acid (IPA), in an animal model of depression based on repeated exposure to unpredictable stress. Rats were divided in groups, and IPA (20 mg/kg), the tricyclic antidepressant imipramine (IMI) (5 mg/kg), or vehicle was administered daily during 3 weeks of repeated exposure to various stressors according to the procedure described by Katz et al [Katz RJ, Roth KA, Carroll BJ (1981): Neurosci Biobehav Rev 5:247-251]. After treatment, rats were evaluated for stress-induced exploratory behavior and killed 24 hr later. Serum corticosterone levels and glucocorticoid receptor (GR) immunoreactivity (IR) in the nuclei of neurons located in the hippocampal subregion CA1 were also measured. Rats exposed to repeated stress showed a lower exploratory behavior score (p < 0.01), higher basal corticosterone levels (p < 0.01), and stronger GR IR in the hippocampus (p < 0.05) than control rats. All of these effects were antagonized by IMI treatment. IPA administration did not affect the behavioral response induced by repeated stress (p < 0.01) but normalized serum corticosterone levels. In addition, IPA treatment produced a decrease in GR IR (p < 0.05 versus control group) that was not modified by exposure to repeated stress.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Indole-pyruvic acid, a tryptophan ketoanalogue, antagonizes the endocrine but not the behavioral effects of repeated stress in a model of depression. 835 66


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