Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is well established that individual rats exhibit marked differences in behavioral responses to a novel environment. Rats that exhibit high rates of locomotor activity and sustained exploration in such an environment also exhibit high concentrations of stress-induced plasma corticosterone, linking this behavior to the stress system. Furthermore, these high-responding (HR) rats, in contrast to their low-responding (LR) counterparts, have a greater propensity to self-administer drugs. Thus, HR rats have been described as "novelty" seeking in that they are more active and explore novel stimuli more vigorously, despite the fact that this elicits in them high stress responses. In this study, we have further characterized the behavior of HR and LR rats in tests of anxiety and characterized their stress responses to either experimenter- or self-imposed stressors. We then investigated the physiological basis of these individual differences, focusing on stress-related molecules, including the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), corticotropin-releasing hormone (CRH) and pro-opiomelanocortin (POMC) in the context of the limbic-hypothalamo-pituitary adrenal axis. We have found that HR rats did not differ from LR in their basal expression of POMC in the pituitary. However, HR rats exhibited higher levels of CRH mRNA in the hypothalamic paraventricular nucleus but lower basal levels in the central nucleus of the amygdala. The basal expression of hippocampal MR is not different between HR and LR rats. Interestingly, the basal expression of hippocampal GR mRNA is significantly lower in HR than in LR rats. This low level of hippocampal GR expression in HR rats appears to be responsible, at least in part, for their decreased anxiety in exploring novelty. Indeed, the anxiety level of LR rats becomes similar to HR rats after the administration into the hippocampus of a GR antagonist, RU38486. These data indicate that basal differences in gene expression of key stress-related molecules may play an important role in determining individual differences in responsiveness to stress and novelty. They point to a new role of hippocampal GR, strongly implicating this receptor in determining individual differences in anxiety and novelty-seeking behavior.
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PMID:Neurobiological correlates of individual differences in novelty-seeking behavior in the rat: differential expression of stress-related molecules. 1099 43

Glucocorticoids have a prominent impact on the maturation of the stress-related neuroendocrine system and on the postnatal establishment of adaptive behaviour. The present study aimed at investigating the stress responsiveness of the hypothalamo-pituitary-adrenocortical (HPA) axis in young and adult rats after neonatal treatment with the synthetic glucocorticoid agonist, dexamethasone. Newborn male Wistar rats were injected s.c. with 1 microg/g dexamethasone on postnatal days 1, 3 and 5. Circulating adrenocorticotropic hormone (ACTH) and corticosterone concentrations were measured in the resting state and following a 30-min cold stress at the age of 10 days, as well as after a 30-min restraint stress at the age of 14 weeks. Also in adults, pituitary and adrenocortical hormone responsiveness was evaluated after i.v. administration of 2 microg/kg corticotropin releasing hormone (CRH). In addition, glucocorticoid (GR) and mineralocorticoid receptor (MR) binding capacities were assessed in the pituitaries of adult rats. The results showed that at day 10 basal ACTH concentration was elevated while the cold stress-evoked ACTH response was attenuated in the dexamethasone-treated rats. As adults, treated rats showed a suppressed elevation of both ACTH and corticosterone plasma concentrations in response to restraint, while basal hormonal concentrations were not altered. There was no difference in the magnitude of the CRH-induced elevation of ACTH and corticosterone concentrations initially; however, the dexamethasone-treated animals showed a prolonged secretion of both hormones. These animals also showed a selective decrease in pituitary GR binding capacity. Neonatal dexamethasone treatment strongly suppressed body weight gain, and adrenal and thymus weights in the early phase of postnatal development. By adulthood, the body and adrenal weights were normalized while thymus weight was greater than in controls. These findings indicate that neonatal dexamethasone treatment permanently alters HPA axis activity by reducing stress responses to cold and restraint probably through supra-pituitary actions, and by decreasing the effectiveness of feedback through a diminished GR binding in the pituitary.
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PMID:Blunted pituitary-adrenocortical stress response in adult rats following neonatal dexamethasone treatment. 1101 43

Low-renin hypertension is common and usually implies increased retention of sodium (Na(+)). In every case of known etiology, there is a mineralocorticoid-induced increase in number of epithelial Na(+) channels (ENaCs) in the collecting duct of the kidney, leading to a state of "hyperENaCactivity." In primary aldosteronism, a result of either an adrenal adenoma or bilateral adrenal hyperplasia, aldosterone itself mediates the increase in ENaC function. A severe form of low-renin hypertension in which a molecular mutation in ENaC prevents removal of the channel from the cell surface, known as Liddle's syndrome, results in increased net ENaC activity but, in this case, independently of an increase in aldosterone. Glucocorticoid remedial aldosteronism, an autosomal dominant form of primary aldosteronism, results from a "new" or chimeric gene for aldosterone synthase. Adrenocorticotropic hormone stimulates its expression as well as secretion of aldosterone. Apparent mineralocorticoid excess results from a molecular mutation that allows cortisol to bind to the mineralocorticoid receptor. Both glucocorticoid remedial aldosteronism and apparent mineralocorticoid excess result in an increase in the number of ENaCs. The question remains whether low-renin essential hypertension is related to an increase in ENaC activity. Low-renin hypertension is most common in black patients, who tend to have lower levels of aldosterone as well as renin, which are features that resemble those found in Liddle's syndrome. Preliminary findings suggest that black patients with low-renin hypertension who are resistant to standard antihypertensive therapy respond favorably to the addition of spironolactone, a mineralocorticoid receptor antagonist that reduces ENaC activity.
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PMID:Low-renin hypertension: more common than we think? 1117 96

We hypothesized that exposure to synthetic glucocorticoid during rapid brain growth (d50-52, birth = 68 days) in fetal guinea pigs modifies hypothalamo-pituitary-adrenal (HPA) function after birth, and that this involves changes in central corticosteroid receptor regulation. On the basis of our previous studies, we proposed that this effect is sex-specific. Pregnant guinea pigs were treated with dexamethasone (1 mg/kg) or vehicle on d50-51 of gestation, and juvenile offspring were euthanized at rest or following isolation stress on postnatal day 18. Dexamethasone increased the length of gestation (1.5 days) and altered body and organ (brain, heart, adrenal) growth. Resting plasma cortisol concentrations were significantly elevated in young male, but not female guinea pigs exposed to dexamethasone as fetuses. In female offspring born to dexamethasone-treated mothers, cortisol responses to isolation stress were attenuated. In males, elevated basal cortisol levels were not increased further by isolation. In the brain, hippocampal glucocorticoid receptor (GR) mRNA levels were significantly lower (10-25%) in females exposed to dexamethasone in utero. In contrast, GR mRNA levels were elevated (10-20%) in males from this prenatal treatment group. Mineralocorticoid receptor mRNA in the limbic system and GR mRNA levels in the pars distalis were unaffected. Pro-opiomelanocortin mRNA was significantly lower (30%) in the male pars intermedia following dexamethasone exposure. In conclusion, prenatal glucocorticoid exposure affects growth and HPA function as well as limbic and hypothalamic GR expression in juvenile offspring, and these effects are highly sex-specific.
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PMID:Prenatal glucocorticoid modifies hypothalamo-pituitary-adrenal regulation in prepubertal guinea pigs. 1130 38

We investigated whether acute stressors regulate functional properties of the hippocampal mineralocorticoid receptor (MR), which acts inhibitory on hypothalamic-pituitary-adrenocortical activity. Exposure of rats to forced swimming or novelty evoked a significant rise in density of MR immunoreactivity in all hippocampal subfields after 24 hr, whereas exposure to a cold environment was ineffective. Time course analysis revealed that the effect of forced swimming on MR peaked at 24 hr and returned to control levels between 24 and 48 hr. In pyramidal neurons of CA2 and CA3, marked rises were already observed after 8 hr. Radioligand binding assays showed that corticotropin-releasing hormone (CRH) injected intracerebroventricularly into adrenalectomized rats also produced a rise in hippocampal MR levels; an effect for which the presence of corticosterone, but not dexamethasone, at the time of injection was a prerequisite. Moreover, pretreatment with the CRH receptor antagonist (d-Phe(12),Nle(21,38),alpha-Me-Leu(37))-CRH(12-41) blocked the effect of forced swimming on hippocampal MR levels. To investigate whether the rise in MR levels had any functional consequences for HPA regulation, 24 hr after forced swimming, a challenge test with the MR antagonist RU 28318 was conducted. The forced swimming exposed rats showed an enhanced MR-mediated inhibition of HPA activity. This study identifies CRH as an important regulator of MR, a pathway with marked consequence for HPA axis regulation. We conclude that the interaction between CRH and MR presents a novel mechanism involved in the adaptation of the brain to psychologically stressful events.
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PMID:Psychological stress increases hippocampal mineralocorticoid receptor levels: involvement of corticotropin-releasing hormone. 1142 9

We have shown in a previous study that high corticosterone levels during repeated immobilization stress result in a reduction of glucocorticoid receptor (GR) mRNA in the hypothalamic paraventricular nucleus (PVN) and the hippocampus. The reduction of GR presumably accounts for loss of or decrease in glucocorticoid-negative feedback, and thus hyperfunction of the hypothalamic-pituitary-adrenocortical (HPA) axis persists during chronic stress. Starvation is a stress state in which the counterregulatory responses against the loss of food occur in the central nervous system. We explored the impact of starvation on the HPA axis, GR and mineralocorticoid receptor (MR) mRNAs in the hippocampus, the PVN, and the anterior pituitary (AP) of rats. Rats were starved for 4 days and sacrificed in the morning. Starved rats showed high levels of plasma corticosterone, whereas neither plasma corticotropin (ACTH), AP proopiomelanocortin (POMC) mRNA nor AP type-1 corticotropin-releasing hormone (CRH) receptor mRNA was altered in the starved rats. In the presence of high corticosterone, starvation resulted in a decrease in both CRH mRNA and type-1 CRH receptor mRNA in the PVN. Consistently, the starved rats did not show any changes in GR mRNA in the hippocampus (CA1-2, CA3, and dentate gyrus), the PVN or the AP despite the elevation of plasma corticosterone. A significant decrease in MR mRNA was seen in the dentate gyrus and the AP, but not in CA1-2, CA3 or PVN. The lack of reduction of GR may be one of the organism's counterregulatory responses during starvation, which allows an intact glucocorticoid negative feedback, thereby resulting in decreased anorectic neuropeptide levels, namely CRH, in the PVN. The results also indicate that GR mRNA in the hippocampus and other brain regions is not solely regulated by circulating glucocorticoids. The mechanism underlying the regulation of GR mRNA in the central nervous system remains to be clarified.
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PMID:Lack of decrease in hypothalamic and hippocampal glucocorticoid receptor mRNA during starvation. 1147 19

We investigated the effects of perinatal maternal malnutrition on the hypothalamo-pituitary-adrenal (HPA) axis activity in both basal and stressful conditions in newborn rats at weaning. Mothers from the control group were fed ad libitum. Mothers exposed to food restriction received 50% (FR50) of the daily intake of pregnant dams during the last week of gestation (Pre group), lactation (Post group) or both periods (PP group) in order to compare the long-term effects of gestational and/or lactational restriction. FR50 reduced the body growth of pups from the Post and PP groups as soon as day 11 until day 21 after birth. At weaning, pups of the Post and PP groups showed reduced adrenal, thymus and liver weights. Although the plasma adrenocorticotropic hormone (ACTH) level was reduced in pups, FR50 affected neither corticotropin-releasing hormone expression and peptide synthesis in the hypothalamus nor proopiomelanocortin expression in the adenohypophysis. Basal circulating levels of corticosterone were not markedly affected by FR50, but free corticosterone concentration was increased in the PP group. Plasma corticosterone-binding globulin (CBG) was decreased in newborns from both the Post and PP groups. Mineralocorticoid receptor gene expression was significantly increased in both CA1 and CA3 hippocampal areas in the PP group. Glucocorticoid receptor gene expression was increased in CA1, CA2 and dentate gyrus hippocampal areas in the Pre group, as well as in CA1, CA3 and DG areas in the Post group. The ether inhalation-induced plasma ACTH increase was weaker in pups from the Post and PP groups. Similarly, the ether inhalation-induced plasma corticosterone increase returned to basal levels in the Post group, or to weaker values than baseline in the PP group 90 min after this stressful procedure. The present work suggests that maternal food restriction during the perinatal period (gestation and lactation) or during lactation only reduces the postnatal somatic growth of pups and disturbs the activity of the HPA axis at weaning under both resting and stress conditions. A reduction in the plasma CBG-binding capacity, associated with a probable increase in hippocampal corticosteroid receptors, could reinforce glucocorticoid-mediated negative feedback and shorten stress-induced activation of the HPA axis in pups at weaning.
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PMID:Perinatal maternal food restriction induces alterations in hypothalamo-pituitary-adrenal axis activity and in plasma corticosterone-binding globulin capacity of weaning rat pups. 1181 34

In humans, an altered control of cortisol secretion was reported in adult men born with a low birth weight making the hypothalamic-pituitary-adrenal (HPA) axis a possible primary target of early life programming. In rats, we have recently shown that maternal food restriction during late pregnancy induces both an intrauterine growth retardation and an overexposure of fetuses to maternal corticosterone, which disturb the development of the HPA axis in offspring. The first aim of this work was to investigate, in adult male rats, whether perinatal malnutrition has long-lasting effects on the HPA axis activity during both basal and stressful conditions. Moreover, as the HPA axis and sympathetic nervous system are both activated by stress, the second aim of this work was to investigate, in these rats, the adrenomedullary catecholaminergic system under basal and stressful conditions. This study was conducted on 4-month-old male rats malnourished during their perinatal life and on age-matched control animals. Under basal conditions, perinatal malnutrition reduced body weight and plasma corticosteroid-binding globulin (CBG) level but increased mineralocorticoid receptor (MR) gene expression in CA1 hippocampal area. After 30 min of restraint, perinatally malnourished (PM) rats showed increased plasma noradrenaline, adrenocorticotropin hormone (ACTH) and corticosterone concentrations similarly as controls, but calculated plasma-free corticosterone concentration was significantly higher and adrenaline level lower than controls. During the phase of recovery, PM rats showed a rapid return of plasma ACTH and corticosterone concentrations to baseline levels in comparison with controls. These data suggest that in PM rats, an elevation of basal concentrations of corticosterone, in face of reduced CBG and probably increased hippocampal MR lead to a much larger impact of corticosterone on target cells that mediate the negative-feedback mechanism on the activities of both the HPA axis and sympathoadrenal one.
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PMID:Perinatal malnutrition programs sympathoadrenal and hypothalamic-pituitary-adrenal axis responsiveness to restraint stress in adult male rats. 1184 73

Traditionally, the role of aldosterone in heart failure was thought to be a result of its effects on epithelial cells where it induces sodium reabsorption and potassium excretion with subsequent haemodynamic effects from intravascular volume expansion. On this basis, spironolactone, a non-selective aldosterone antagonist, has been used for the treatment of congestive heart failure to block aldosterone-mediated effects in epithelial cells. The Randomized Aldactone Evaluation Study (RALES), in which spironolactone was added to existing therapy in patients with heart failure, showed a significant reduction in morbidity and mortality. These results suggest that the role of aldosterone in the pathophysiology of cardiovascular disease may be more complex than previously recognised. There now is extensive experimental and growing clinical evidence for an important physiological role for aldosterone in the pathology of cardiac and renal disease. Classical effects of aldosterone are mediated via its nuclear receptor. Novel non-epithelial effects of aldosterone are mediated via a second messenger system, which involves activation of the sodium/hydrogen antiporter. These effects of aldosterone have been demonstrated in the kidney, vascular smooth muscle cell and leukocytes, and in the regulation of rapid corticotropin suppression. It has been hypothesised that cardiac damage induced by aldosterone is independent of the presence of hypertension. In support of this, experimental evidence demonstrates that cardiovascular damage induced by aldosterone can be prevented by administration of a selective mineralocorticoid receptor antagonist. These findings suggest the dissociation between cardiovascular lesions and high blood pressure, and highlight the importance of aldosterone in the pathological changes.
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PMID:Rationale for the use of aldosterone antagonists in congestive heart failure. 1192 27

Dehydration, a classic homeostatic stressor in rats, leads to a series of well characterized endocrine responses including stimulation of the hypothalamo-pituitary-adrenal (HPA) axis. In this study, the hypothesis to be tested was that a 50% maternal food restriction (FR50) in late gestation and lactation may have long-term repercussions on HPA axis responsiveness to dehydration in offspring. For this purpose, we studied HPA axis activity in 4-month-old control (C) and perinatally malnourished male rats after a 72-hour water deprivation period. Furthermore, we investigated the long-lasting effects of perinatal maternal malnutrition on the basal activity of the HPA axis. Under basal conditions, rats exposed to perinatal malnutrition showed reduced body weight, enhanced mineralocorticoid receptor (MR) mRNA levels in CA2 and CA3 hippocampal areas, but decreased glucocorticoid receptor (GR) mRNA levels in CA1, CA3 and dentate gyrus (DG) areas. In contrast, the levels of corticotropin-releasing hormone (CRH) and vasopressin (VP) mRNAs in the hypothalamic paraventricular nucleus (PVN) as well as of VP mRNA in the supraoptic nucleus (SON) were unaffected by maternal undernutrition. Expression of proopiomelanocortin (POMC) in the adenohypophysis was significantly enhanced, whereas prohormone convertase-1 (PC1) was not affected. Perinatal malnutrition reduced absolute adrenal weight but did not affect circulating levels of adrenocorticotropin (ACTH), corticosterone and free corticosterone as well as corticosteroid-binding globulin (CBG) binding capacity. Seventy-two hours of dehydration induced a decrease in body weight and CRH mRNA levels in PVN of controls as well as of FR50 rats, but also led to a rise in plasma corticosterone and free corticosterone without changing CBG binding capacity. Dehydration also induced an increase in adenopituitary POMC (C) and PC1 (FR50), PVN and SON VP (C) and GR in CA1 hippocampal area (FR50) mRNA levels and plasma ACTH (C), but a decrease in MR in DG (C) and GR in CA3 and DG (C) mRNA levels. We conclude that maternal food restriction during the perinatal period affects (1) the adult basal activity of the HPA axis with mainly opposite effects on hippocampal MR and GR gene expression and an increase in adenopituitary POMC gene expression, and (2) the responsiveness to water deprivation in adults. In the latter case, the rise in plasma ACTH levels, adenopituitary POMC gene expression, hypothalamic VP gene expression, and the decrease in hippocampal MR gene expression in DG and GR gene expression in CA3 and DG observed in controls are lacking in FR50 rats. In contrast, drastic adenopituitary PC1 gene expression occurred in FR50 rats but not in control animals.
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PMID:Altered control of the hypothalamo-pituitary-adrenal axis in adult male rats exposed perinatally to food deprivation and/or dehydration. 1241 41


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