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)

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

Plasma levels of the N-terminal peptide of proopiomelanocortin (NPP) were measured in rainbow trout, Salmo gairdneri, following treatment of handling stress with or without administration of dexamethasone, adaptation to white and black background, and maintenance on a constant light/dark cycle. Effects of exogenously administered NPP on plasma constituents were also examined to provide insight into the biological significance of NPP. Thirty minutes of handling stress in shallow water had no effect on plasma levels of NPP during and after the stress period, whereas significant increases in plasma cortisol and glucose were observed. Intraperitoneal administration of dexamethasone blocked the stress-induced elevation of plasma levels of cortisol and caused a depression of plasma NPP. No difference was observed in plasma levels of NPP between trout adapted to a white background and those adapted to a black background. No diurnal changes in NPP were observed under an artificial light/dark cycle (14L/10D light cycle, 0500-1900 hr light) in May and September. Thus, plasma levels of NPP were considerably constant under various physiological conditions, and no synchronism was observed between plasma NPP and cortisol, although NPP modifies the corticotropin-induced release of cortisol from the interrenal. Plasma constituents such as cortisol, total protein, albumin, plasma amino nitrogen, glucose, free fatty acid, ketone body, sodium, potassium, calcium, and magnesium were not altered by intraperitoneal injections of NPP (1 or 10 micrograms) once daily for 6 days (total of six injections) or once every other day for 28 days (14 injections). High concentrations of NPP were found in the plasma 24 hr after cessation of the serial injections of NPP (10 micrograms), suggesting slow metabolic clearance of the peptide.
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PMID:Plasma profiles of the N-terminal peptide of proopiomelanocortin in the rainbow trout with reference to stress. 229 28

It has been recently demonstrated that sex steroids can negatively regulate beta-endorphin content as well as proopiomelanocortin (POMC) mRNA levels in the rat basal hypothalamus. In order to verify whether or not all the POMC neurons are equally affected by sex steroids, we arbitrarily divided the arcuate nucleus rostro-caudally into four equal portions and used an in situ hybridization technique to evaluate POMC gene expression in these different regions of the arcuate nucleus in the female rat. It was shown that ovariectomy induced an increase in mRNA levels in the most rostral region of the arcuate nucleus, an effect which was reversed by the concurrent administration of estradiol and dihydrotestosterone. On the other hand, estrogen administration to ovariectomized animals produced a marked depression of mRNA levels in all the regions of the arcuate nucleus with the exception of the most caudal one. These results suggest that sex steroids exert their action in subpopulations of POMC neurons.
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PMID:Regulation of proopiomelanocortin messenger ribonucleic acid content by sex steroids in the arcuate nucleus of the female rat brain. 238 58

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 mechanism of the circadian hormonal secretions is still obscure. The cyclic activity of the hypothalamus-ACTH-adrenal (H-A-A) axis is perhaps the most studied. ACTH derives with other peptides from a common precursor, proopiomelanocortin. ACTH secretion is under inhibitory and stimulatory influences. The inhibitory influence is mediated by the negative feed-back of adrenal corticosteroids and by the short loop feed-back of ACTH on its own secretion. The stimulatory influence is exerted by the hypothalamic corticotropin releasing factor (CRF), recently isolated in the ovine hypothalamus. CRF is regulated by various neurotransmitttttorial activities. Serotonin and acetylcholine play a stimulatory role, while dopamine and norepinephrine, in particular, seem to exert an inhibitory tonic control. The increased ACTH secretion in stress-response seems to be mediated by a reduction of this tone. However, the neurotransmitorial modifications involved in the rhythmic secretion of the H-A-A axis are still obscure. So chrononeuroendocrine study of the H-A-A axis in various psychoneuroendocrine diseases is of great interest in clearing up the neurotransmitorial mechanisms of this rhythm. Primary depression represents an interesting model being characterized by monoaminergic neurotransmitorial alterations. We have observed in this pathology an increase of the H-A-A axis activity and an alteration of the circadian cortisol profile characterized by an increase both in numeric and quantitative secretory bursts.
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PMID:Chrononeuroendocrine perspectives of ACTH and related peptides. 613 88

Antidepressant drugs have in common a delayed onset of clinical efficacy. In rats, long-term, daily administration of four different types of clinically effective antidepressant drugs results in decreased corticotropin releasing hormone (CRH) mRNA expression levels in the hypothalamic paraventricular nucleus (PVN). Because a subpopulation of neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (Arc) projects to the PVN, we measured NPY and POMC mRNA expression in the Arc using in situ hybridization histochemistry at several time points following daily administration of four different antidepressant drugs. After 14 and 56 days of imipramine treatment, Arc NPY mRNA levels are decreased to 85% and 75% of control levels, but are unchanged compared to control after one or five days of treatment. Arc POMC mRNA levels are unchanged compared to controls at 1, 5, 14, or 56 days following imipramine treatment. Unlike after imipramine, Arc NPY and POMC mRNA levels are increased significantly to 134-172% of control following 56-day treatment with the antidepressant drugs fluoxetine, phenelzine, or idazoxan. The divergent effects of imipramine vs the other 3 antidepressant drugs on Arc NPY mRNA expression are similar to the pattern of changes in tyrosine hydroxylase (TH) mRNA expression levels in the locus coeruleus (LC) using the same experimental paradigm, but are different from the unidirectional depressive effects of all four drugs on CRH mRNA expression in the PVN. Thus, the Arc NPY and LC noradrenergic systems may act coordinately in mediating antidepressant effects. The present data are consistent with the delayed onset of clinical efficacy for antidepressant drugs, and suggest that Arc NPY and POMC neurotransmitter systems play a role in the pathophysiology of depression.
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PMID:Effects of long-term treatment with antidepressant drugs on proopiomelanocortin and neuropeptide Y mRNA expression in the hypothalamic arcuate nucleus of rats. 873 33

The purpose of this study was to investigate the effects of acute and repeated electroconvulsive shock (ECS) on corticotropin releasing factor (CRF), proopiomelanocortin (POMC) and proenkephalin (PENK) gene expression in selected regions of the brain and pituitary of the rat. Acute ECS increased CRF gene expression in the paraventricular nucleus (PVN) by 20%, an effect that was further enhanced to 38% when rats received repeated ECS treatment. Acute and repeated ECS increased POMC gene expression in the arcuate nucleus (ARC) by 49-59% but failed to alter these mRNA levels in the anterior lobe (AL) of the pituitary gland. PENK gene expression was increased by 35% in the nucleus accumbens (NA) and by 180% the ventromedial nucleus (VMN) after acute or repeated ECS treatment but no significant changes were found in the PVN or striatum (ST). Taken together, these results indicate a differential CRF and opioid gene expression regulation after acute or repeated ECS treatment that may be relevant to their therapeutic or side effects in depression.
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PMID:Acute and repeated ECS treatment increases CRF, POMC and PENK gene expression in selected regions of the rat hypothalamus. 959 51

The hypothalamic-pituitary-adrenal axis exerts profound, multilevel inhibitory effects on the female reproductive system. Corticotropin-releasing hormone (CRH) and CRH-induced proopiomelanocortin peptides inhibit hypothalamic gonadotropin-releasing hormone secretion, whereas glucocorticoids suppress pituitary luteinizing hormone and ovarian estrogen and progesterone secretion and render target tissues resistant to estradiol. The hypothalamic-pituitary-adrenal axis is thus responsible for the "hypothalamic" amenorrhea of stress, which is also seen in melancholic depression, malnutrition, eating disorders, chronic active alcoholism, chronic excessive exercise, and the hypogonadism of the Cushing syndrome. Conversely, estrogen directly stimulates the CRH gene promoter and the central noradrenergic system, which may explain adult women's slight hypercortisolism; preponderance of affective, anxiety, and eating disorders; and mood cycles and vulnerability to autoimmune and inflammatory disease, both of which follow estradiol fluctuations. Several components of the hypothalamic-pituitary-adrenal axis and their receptors are present in reproductive tissues as autacoid regulators. These include ovarian and endometrial CRH, which may participate in the inflammatory processes of the ovary (ovulation and luteolysis) and endometrium (blastocyst implantation and menstruation), and placental CRH, which may participate in the physiology of pregnancy and the timing of labor and delivery. The hypercortisolism of the latter half of pregnancy can be explained by high levels of placental CRH in plasma. This hypercortisolism causes a transient postpartum adrenal suppression that, together with estrogen withdrawal, may partly explain the depression and autoimmune phenomena of the postpartum period.
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PMID:Interactions between the hypothalamic-pituitary-adrenal axis and the female reproductive system: clinical implications. 969 32

Neuroendocrine activation during stress is affected by many factors contributing to the variability of the stress response. The present study was aimed at evaluating long-term changes in hypothalamo-pituitary-adrenocortical (HPA) axis function and in hedonic behavior in adult offspring prenatally stressed by maternal food restriction, with attention on possible gender differences. Adult offspring were blood sampled via a tail artery cannula. Prenatally stressed females had significantly higher adrenal weights compared to males. Plasma ACTH levels, which rose in response to acute stress induced by handling, were significantly higher in females compared to those in males. A similar pattern was found in plasma corticosterone. The rise in ACTH levels was more pronounced in prenatally stressed rats though the rise in corticosterone failed to be modified. Corticotropin releasing hormone (CRH) and proopiomelanocortin mRNA levels in the hypothalamic paraventricular nucleus and anterior pituitary, respectively, were found to be unchanged. The present experiments failed to reveal a decrease in hedonic behavior in prenatally stressed rats. In contrast, in male offspring a tendency to a higher sucrose preference was observed. These data together with observed changes in hormone and CRH mRNA levels indicate that the gestational stress used did not result in a depression-like state in adult offspring.
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PMID:Hypothalamo-pituitary-adrenocortical axis function and hedonic behavior in adult male and female rats prenatally stressed by maternal food restriction. 1218 80

Stress activates the central and peripheral components of the stress system, i.e., the hypothalamic-pituitary-adrenal (HPA) axis and the arousal/sympathetic system. The principal effectors of the stress system are corticotropin-releasing hormone (CRH), arginine vasopressin, the proopiomelanocortin-derived peptides alpha-melanocyte-stimulating hormone and beta-endorphin, the glucocorticoids, and the catecholamines norepinephrine and epinephrine. Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks and positive social interactions. By contrast, inappropriate responsiveness of the stress system may impair growth and development, and may account for a number of endocrine, metabolic, autoimmune and psychiatric disorders. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors and the timing of the stressful event(s), given that prenatal life, infancy, childhood and adolescence are critical periods characterized by increased vulnerability to stressors. The developing brain undergoes rapid growth and is characterized by high turnover of neuronal connections during the prenatal and early postnatal life. These processes and, hence, brain plasticity, slow down during childhood and puberty, and plateau in young adulthood. Hormonal actions in early life, and to a much lesser extent later, can be organizational, i.e., can have effects that last for long periods of time, often for the entire life of the individual. Hormones of the stress system and sex steroids have such effects, which influence the behavior and certain physiologic functions of individuals for life. Exposure of the developing brain to severe and/or prolonged stress may result in hyperactivity/hyperreactivity of the stress system, with resultant amygdala hyperfunction (fear reaction), decreased activity of the hippocampus (defective glucocorticoid-negative feedback, cognition), and the mesocorticolimbic dopaminergic system (dysthymia, novelty-seeking, addictive behaviors), hyperactivation of the HPA axis (hypercortisolism), suppression of reproductive, growth, thyroid and immune functions, and changes in pain perception. These changes may be accompanied by abnormal childhood, adolescent and adult behaviors, including excessive fear ('inhibited child syndrome') and addictive behaviors, dysthymia and/or depression, and gradual development of components of the metabolic syndrome X, including visceral obesity and essential hypertension. Prenatal stress exerted during the period of sexual differentiation may be accompanied by impairment of this process with behavioral and/or somatic sequelae. The vulnerability of individuals to develop varying degrees and/or components of the above life-long syndrome is defined by as yet unidentified genetic factors, which account for up to 60% of the variance. CRH has marked kindling and glucocorticoids have strong consolidating properties, hence both of these hormones are crucial in development and can alone produce the above syndrome. CRH and glucocorticoids may act in synergy, as in acoustic startle, while glucocorticoids may suppress or stimulate CRH, as in the hypothalamus and amygdala, respectively. A CRH type 1 receptor antagonist, antalarmin, inhibits both the development and expression of conditioned fear in rats, and has anxiolytic properties in monkeys. Profound stressors, such as those from sexual abuse, may elicit the syndrome in older children, adolescents and adults. Most frequently, chronic dysthymia and/or depression may develop in association with gastrointestinal complaints and/or the premenstrual tension syndrome. A lesser proportion of individuals may develop the classic posttraumatic stress disorder, which is characterized by hypocortisolism and intrusive and avoidance symptoms; in younger individuals it may present as dissociative personality disorder.
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PMID:Pediatric stress: hormonal mediators and human development. 1264 70


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