Showing papers on "Corticosterone published in 1995"
TL;DR: The results indicate that the reversible atrophy induced by 21 days of daily restraint stress requires corticosterone secretion and that excitatory mechanisms involving N-methyl-D-aspartate receptors play a major role in driving the atrophy.
863 citations
Journal Article•
TL;DR: It is suggested that endocrine factors released during stress modulate leukocyte trafficking and result in the redistribution of leukocytes between the blood and other immune compartments, which may significantly affect the ability of the immune system to respond to potential or ongoing immune challenge.
Abstract: Immune cell trafficking is crucial to the performance of the surveillance as well as effector functions of the immune system Because immune cells travel between tissues through the bloodstream, the numbers and proportions of leukocytes in the circulation provide an important representation of the state of leukocyte distribution in the body The studies described here examine significant and selective changes in numbers and percentages of peripheral blood leukocyte subpopulations in the rat These changes were rapidly induced under conditions of mild acute stress Stress-induced increases in plasma corticosterone were accompanied by a significant decrease in numbers and percentages of lymphocytes, and by an increase in numbers and percentages of neutrophils flow cytometric analysis revealed that B cell, NK cell, and monocyte numbers showed a greater stress-induced decrease than did T cells All stress-induced changes were observed during the light (inactive) as well as the dark (active) period of the animal's diurnal cycle Importantly, the stress-induced changes in leukocyte numbers and percentages were rapidly reversed upon the cessation of stress Furthermore, the effects of stress were largely dependent on adrenal hormones, because the magnitude of the stress-induced changes was significantly reduced in adrenalectomized animals Moreover, administration of corticosterone to adrenalectomized animals resulted in a close replication of stress-induced changes observed in adrenal-intact animals These results suggest that endocrine factors released during stress modulate leukocyte trafficking and result in the redistribution of leukocytes between the blood and other immune compartments Such a redistribution may significantly affect the ability of the immune system to respond to potential or ongoing immune challenge
705 citations
TL;DR: These results are consistent with a model in which adrenocortical secretion plays a permissive role in enabling another agent, namely, excitatory amino acids, to produce the final effect.
588 citations
TL;DR: It is found that prenatal stress prolongs stress-induced corticosterone secretion in adult rats, which was attributed to the observed decrease in central corticosteroid receptors; adoption, irrespective of the stress experience of the foster mother, reverses the effects of prenatal stress; and adoption per se increases maternal behavior and decreases the stress- induced cortic testosterone secretion peak in the adult offspring.
Abstract: The development of the organism is subjected to critical and complex influences during the perinatal period. Prenatal and postnatal stresses can have different long-term behavioral effects, and appropriate postnatal manipulations can counteract the behavioral effects of prenatal stress. In the present study, we investigated the involvement of changes in the activity of the hypothalamo-pituitary-adrenal (HPA) axis in the long-term effects of prenatal and postnatal events and of interactions between them. We investigated stress-induced corticosterone secretion and hippocampal corticosteroid receptors in male adult rats submitted to prenatal and/or postnatal manipulations. Repeated restraint during the last week of pregnancy was used as prenatal stressor, and adoption at birth was used to change the postnatal environment. We found that (1) prenatal stress prolongs stress-induced corticosterone secretion in adult rats, which was attributed to the observed decrease in central corticosteroid receptors; (2) adoption, irrespective of the stress experience of the foster mother, reverses the effects of prenatal stress; and (3) adoption per se increases maternal behavior and decreases the stress- induced corticosterone secretion peak in the adult offspring. In conclusion, certain prenatal and postnatal manipulations appear to have opposite long-term effects on the activity of the HPA axis, and adoption, probably by modifying maternal behavior, can protect against the effects of prenatal stress. Thus, changes in the activity of the HPA axis may be one of the biological substrates of the long-term effects of certain perinatal events.
576 citations
TL;DR: Elevated glucocorticoid levels mediate the effects of stress on spatial memory in older animals, suggesting that elevation of corticosterone levels mediates the effect of stress in animals that had been previously adrenalectomized.
Abstract: Prolonged treatment with stress levels of corticosterone has been reported to produce changes in the hippocampus. In the experiments reported here, we examined for functional and morphological consequences of this treatment. First, young adult or mid-aged male Long-Evans rats were treated for either 1 or 3 months with corticosterone, at a dose sufficient to mimic the elevated hormone levels observed following exposure to mild stress. Two weeks following the termination of treatment, the animals were tested in the Morris water maze to assess spatial learning. No behavioral deficits were observed after 1 month of treatment. A 3 month treatment period also had no effect in young rats, but produced a learning impairment in the mid-aged rats. We then examined whether the effect of elevated corticosterone in mid-aged animals could be produced by a physiological stressor. Mid-aged rats were maintained for 6 months under conditions of low or high social stress. Six months of exposure to high social stress produced significant spatial learning impairments in the Morris water maze. These effects were absent in high social stress animals that had been previously adrenalectomized (with low-level corticosterone replacement), suggesting that elevated glucocorticoid levels mediate the effects of stress on spatial memory in older animals. In a final experiment, mid-aged rats were treated with corticosterone at levels that mimicked those naturally occurring at the diurnal peak (medium-B: 12–17 micrograms/dl) or in response to stress (high-B: 25–32 micrograms/dl). Only rats exposed to high levels of corticosterone demonstrated impaired performance in the Morris water maze.(ABSTRACT TRUNCATED AT 250 WORDS)
537 citations
TL;DR: The effect of prenatal stress on HPA function is substantially more marked in females than in males, and a similar pattern of effects on H PA activity has been reported for prenatal alcohol exposure.
484 citations
TL;DR: The VBS colony model appears to enable rat groups to produce natural, stress-engendering, social interactions that constitute a particularly relevant model for investigating the behavioral, neural, and endocrine correlates of chronic stress.
469 citations
TL;DR: Results confirm that SF-1 is an important regulator of adrenal and gonadal development, but its regulation of steroid hydroxylase expression in vivo remains to be established.
Abstract: The orphan nuclear receptor steroidogenic factor 1 (SF-1) is expressed in the adrenal cortex and gonads and regulates the expression of several P450 steroid hydroxylases in vitro. We examined the role of SF-1 in the adrenal glands and gonads in vivo by a targeted disruption of the mouse SF-1 gene. All SF-1-deficient mice died shortly after delivery. Their adrenal glands and gonads were absent, and persistent Mullerian structures were found in all genotypic males. While serum levels of corticosterone in SF-1-deficient mice were diminished, levels of adrenocorticotropic hormone (ACTH) were elevated, consistent with intact pituitary corticotrophs. Intrauterine survival of SF-1-deficient mice appeared normal, and they had normal serum level of corticosterone and ACTH, probably reflecting transplacental passage of maternal steroids. We tested whether SF-1 is required for P450 side-chain-cleavage enzyme (P450scc) expression in the placenta, which expresses both SF-1 and P450scc, and found that in contrast to its strong activation of the P450scc gene promoter in vitro, the absence of SF-1 had no effect on P450scc mRNA levels in vivo. Although the region targeted by our disruption is shared by SF-1 and by embryonal long terminal repeat-binding protein (ELP), a hypothesized alternatively spliced product, we believe that the observed phenotype reflects absent SF-1 alone, as PCR analysis failed to detect ELP transcripts in any mouse tissue, and sequences corresponding to ELP are not conserved across species. These results confirm that SF-1 is an important regulator of adrenal and gonadal development, but its regulation of steroid hydroxylase expression in vivo remains to be established.
454 citations
TL;DR: It is found that sex steroids modulate HPA activity and it is suggested that the observed effects of these steroids on hippocampal MR may underlie their concerted mechanism of action in inducing an enhanced activity at the period of late pro-oestrus.
Abstract: The present study examined the association between hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-ovarian axes. HPA activity determined by plasma levels of adrenocorticotropin (ACTH) and corticosterone (B) was assessed in intact female rats as a function of oestrous cycle stage under resting conditions and after exposure to a 20 min restraint stress. To delineate the roles of oestradiol and progesterone in HPA axis modulation, plasma concentrations of ACTH and B were determined in ovariectomised (OVX) animals treated with oestradiol and/or progesterone under resting conditions and during exposure to the stress of a novel environment. The effects of these steroid treatments on the transcription and/or binding properties of the two corticosteroid receptors, the mineralocorticoid (MR) and glucocorticoid (GR) receptors, were also examined in hippocampal tissue, (i) Fluctuations in basal and stress-induced plasma ACTH and B concentrations were found during the oestrous cycle with highest levels at late pro-oestrus. (ii) In OVX steroid-replaced animals, basal and stress-induced activity was enhanced in oestradiol and oestradiol plus progesterone-treated animals compared with OVX controls. (iii) Cytosol binding assays revealed an oestradiol-induced decrease in hippocampal MR capacity. This decrease appears to be due to an effect of the steroid on MR transcription as in situ hybridisation analysis of MR mRNA showed an oestradiol-induced decrease in MR transcript in all hippocampal subfields. (iv) Treatment of oestradiol-primed animals with progesterone reversed the oestradiol-induced decrease in hippocampal MR capacity. Data from MR mRNA hybridisation in situ experiments indicate that this reversal may be due to an antagonism of the oestradiol effect on MR transcription. (v) Progesterone treatment with or without prior oestradiol-priming induced a significant decrease in the apparent binding affinity of hippocampal MR. We show that progesterone and its 11 beta-hydroxylated derivative have a high affinity for the hippocampal MR. (vi) Neither oestradiol nor progesterone affected GR binding parameters in the hippocampus. In conclusion, we find that sex steroids modulate HPA activity and suggest that the observed effects of these steroids on hippocampal MR may underlie their concerted mechanism of action in inducing an enhanced activity at the period of late pro-oestrus.
393 citations
TL;DR: The data indicate that a CORT-mediated decrease in hippocampal and hypothalamic glucocorticoid receptor mRNA levels is not the only mechanism contributing to the maintenance of a robust HPA response after repeated stress and postulates that the relative shift from CRH to AVP in the PVN after repeated Stress is mediated by both a greater sensitivity of AVP to CORT negative feedback and Cort-independent mechanisms.
Abstract: Hypothalamic-pituitary-adrenal (HPA) responses remain intact or increase after chronic or repeated stress despite robust levels of circulating glucocorticoids that would be expected to restrain the responsiveness of the axis. The purpose of this study was to determine whether chronic stress altered corticosteroid receptor messenger RNA (mRNA) levels at any locus known to mediate glucocorticoid feedback on HPA function (i.e. hippocampus or hypothalamus), whether such effects were glucocorticoid dependent, and whether changes in corticosteroid receptor function could potentially contribute to the putative shift from corticotropin-releasing hormone (CRH) to arginine vasopressin (AVP) in the hypothalamic paraventricular nucleus (PVN) in the modulation of pituitary adrenal function occurring during chronic stress. We compared the stress responsiveness of sham-operated rats to that of adrenalectomized rats using a moderate dose of corticosterone (CORT) pellet replacement (ADX + CORT group). Acute immobilization caused a significant increase in CRH, but not AVP, mRNA levels in the parvocellular PVN in sham rats. The ADX + CORT group showed significantly greater increases in both CRH and AVP mRNA levels in the PVN compared to sham rats. These data indicate that PVN AVP mRNA levels are more sensitive to glucocorticoid negative feedback than are the levels of CRH mRNA. In repeated stress, the sham groups showed robust increases in PVN CRH and AVP mRNA levels despite high levels of plasma CORT. The rise in AVP mRNA levels was greater than that in CRH mRNA. Type II glucocorticoid receptor mRNA in the hippocampus and PVN was decreased in the repeatedly stressed sham group. These data suggest a decrease in the CORT negative feedback restraint of PVN CRH and AVP mRNA levels repeated stress and a persistence of relatively greater responsiveness of AVP mRNA levels to CORT negative feedback. After repeated stress in ADX+CORT rats, both PVN CRH and AVP mRNA levels showed robust responses, with a relatively greater increase in AVP mRNA. These data indicate that a CORT-mediated decrease in hippocampal and hypothalamic glucocorticoid receptor mRNA levels is not the only mechanism contributing to the maintenance of a robust HPA response after repeated stress. Similarly, we postulate that the relative shift from CRH to AVP in the PVN after repeated stress is mediated by both a greater sensitivity of AVP to CORT negative feedback and CORT-independent mechanisms.
371 citations
TL;DR: Comparisons of the increases in plasma levels of corticosterone following capture in several taxa of arctic birds indicated that suppression of the adrenocortical response to acute stress was not ubiquitous, and comparative data from free-living arctic Birds suggest an ecological basis for modulation of the cortisol responses to stress.
Abstract: There is considerable evidence that the increases in circulating corticosterone levels following acute stress, such as sudden storms, can trigger facultative behavioral patterns designed to maximize survival. During the breeding season, adrenocortical responses to aseasonal storms may trigger facultative behavioral patterns resulting in temporary disruption of nesting. A renesting cycle often follows when conditions become favorable again. However, in arctic ecosystems the brief breeding season limits the capacity of most avian populations to renest, and yet spring weather may be extreme. This led to the hypothesis that arctic birds may down-regulate their sensitivity to acute stress (such as severe storms) so that breeding can begin and be completed before the first storms of autumn (only 6–8 weeks later). To test this we have used the “stress-series protocol” that takes advantage of the fact that capture, handling and restraint constitutes a more-or-less equal stress among all vertebrate species, and that corticosterone concentrations in small blood samples collected during the first hour post-capture indicate sensitivity of the hypothalamo-adenohypophysial- adrenal axis to acute stresses in general. Comparisons of the increases in plasma levels of corticosterone following capture in several taxa of arctic birds indicated that suppression of the adrenocortical response to acute stress was not ubiquitous. Although some species did show low amplitude responses of the circulating corticosterone increase during the stress series protocol, others did not, and some (especially males) showed an increase in sensitivity to acute stress. Additional hypotheses were suggested as follows: 1) species with greater body mass have larger relative energy reserves and would be more able to resist acute stresses than smaller energy reserves and would be more able to resist acute stresses than smaller species; 2) short-lived birds with an expectancy of one or two breeding seasons should be more resistant to acute stress than long-lived birds that may have many attempts at successful breeding; 3) resistance of the adrenocortical response to stress is a function of the degree of parental care provided by the individual (also takes into account sex differences in parental investment). Correlations of the maximum corticosterone level and the ratio of maximum to minimum corticosterone levels generated during the stress series protocol with body mass and longevity were not significant. However, maximum corticosterone level was significantly lower in birds providing most parental care and almost significant for the ratio of maximum to minimum corticosterone levels. These comparative data from free-living arctic birds suggest an ecological basis for modulation of the adrenocortical responses to stress. In at least one species, up-regulation of the response appears to involve a change in sensitivity to glucocorticosteroid feedback. Further investigations will explore neuroendocrine mechanisms further in the light of these ecological bases.
TL;DR: The work reported here shows that both neuronal and physiological responses adapt to a repeated stress, but that in both cases this has highly specific components.
TL;DR: Investigation of the long-term consequences of neonatal endotoxin exposure on hypothalamic-pituitary-adrenal axis (HPA) function in Long-Evans rats found that exposure to gram-negative LPS in early life can alter the development of neural systems which govern endocrine responses to stress and may thereby predispose individuals to stress-related pathology.
Abstract: The long-term consequences of neonatal endotoxin exposure on hypothalamic-pituitary-adrenal axis (HPA) function were assessed in adult female and male Long-Evans rats. At 3 and 5 d of age, pups were administered endotoxin (Salmonella enteritidis, 0.05 mg/kg, i.p.) at a dose that provokes a rapid and sustained physiological response, but with no mortality. As adults, neonatally endotoxin-treated animals exhibited significantly greater adrenocorticotrophic hormone (ACTH) and corticosterone responses to restraint stress than controls. In addition, dexamethasone pretreatment was less effective in suppressing ACTH responses to restraint stress in endotoxin-treated animals than in controls, suggesting decreased negative-feedback sensitivity to glucocorticoids. Neonatal endotoxin treatment elevated resting-state median eminence levels of corticotropin-releasing hormone (CRH) and arginine vasopressin in adult male animals, and arginine vasopressin in both adult males and females. Neonatal exposure to endotoxin also increased CRH mRNA expression in the paraventricular nucleus of the hypothalamus of adult males, with no difference in females. Finally, glucocorticoid receptor density was reduced across a wide range of brain regions in the neonatal endotoxin-treated, adult animals. These data illustrate the interactive nature of immune and endocrine systems during development. It appears that endotoxin exposure during critical stages of development decreases glucocorticoid negative-feedback inhibition of ACTH secretagogue synthesis, thus increasing HPA responsiveness to stress. The implication of these findings is that exposure to gram-negative LPS in early life can alter the development of neural systems which govern endocrine responses to stress and may thereby predispose individuals to stress-related pathology.
TL;DR: The results suggest that glucocorticoids control stress-induced sensitization by changing the sensitivity of the mesencephalic dopaminergic transmission to drugs of abuse.
Abstract: Repeated exposures to stress sensitize motor and addictive effects of drugs of abuse. Recently, it has been shown that stress-induced behavioral sensitization depends on the secretion of glucocorticoids. We investigated if sensitization of dopamine-dependent effects of psychostimulants and opioids was influenced by glucocorticoid. Sensitization of the dopaminergic response to drugs is considered the neural substrate of behavioral sensitization and has been implicated in vulnerability to drug abuse. Dopamine-dependent effects of psychostimulants and opioids were evaluated by injecting either amphetamine into the nucleus accumbens (10 micrograms/side) or morphine into the ventral tegmental area (VTA) (1 microgram/side). The locomotor response to psychostimulants and opioids injected in these brain areas depends on the mesencephalic dopaminergic transmission. Drug-induced locomotion was compared in male rats in which corticosterone secretion was either in +tct or experimentally suppressed by an adrenalectomy associated with a substitutive treatment reproducing basal levels of the hormone. Eight days of food restriction (80% of the initial body weight) were used as a stressor. Suppression of stress-induced corticosterone secretion abolished food restriction-induced sensitization of the locomotor effects of intra-accumbens amphetamine and intra-VTA morphine. This effect was corticosterone dependent since the restoration of corticosterone levels in the range of those induced by stress totally reinstates sensitization. Our results suggest that glucocorticoids control stress-induced sensitization by changing the sensitivity of the mesencephalic dopaminergic transmission to drugs of abuse. Since dopaminergic effects of drugs are related to their addictive properties, secretion of glucocorticoids may be one of the factors determining the enhanced vulnerability to drugs observed in stressed subjects.
TL;DR: These studies suggest that Type I receptors, with a high affinity for corticosterone, and Type II receptors, having a lower affinity for cortisol, form a two-level recognition system to modulate induced synaptic plasticity in opposite directions in the dentate gyrus and possibly also in Ammon's horn.
TL;DR: It is postulated that the CRH and ACTH responses to a low dose of endotoxin are mediated by vagal afferents, and the responses to the high dose ofascular endotoxin involve additional neuronal or humoral pathways.
Abstract: In order to assess the possibility that endotoxin-induced activation of the hypothalamus-pituitary-adrenal (HPA) axis is mediated by vagal afferents, we studied the effects of transection of the vagal nerves on endotoxin-induced Fos expression in hypothalamic corticotropin-releasing hormone (CRH) neurons and plasma ACTH and corticosterone responses. Groups of rats were subjected to sham surgery, complete subdiaphragmatic vagotomy (SVGX), or selective transection of the hepatic branch (HVGX). Two weeks after surgery, endotoxin or saline was injected i.p. and rats were sacrificed by decapitation two hours later. SVGX blocked or attenuated the ACTH response to 20 and 250 micrograms/kg endotoxin, respectively. HVGX did not suppress the ACTH response to either endotoxin dose. In addition, corticosterone responses were not affected by SVGX or HVGX. The endotoxin-induced Fos expression in CRH neurons was suppressed in SVGX, but not in HVGX animals. These observations lead us to postulate that the CRH and ACTH responses to a low dose of endotoxin are mediated by vagal afferents. The responses to a high dose of endotoxin involve additional neuronal or humoral pathways.
TL;DR: The long term increase in free CORT reported here may play an important role in mediating some of the effects produced by IS as well as those produced by other acute stressors.
Abstract: Adrenal glucocorticoids play an important role in mediating many of the behavioral and physiological effects of exposure to stressors. Focus has been primarily on the acute stress-induced rise in glucocorticoids [corticosterone (CORT) in the rat]. There are reports, however, that exposure to chronic stressors can produce an increase in basal CORT and a decrease in corticotropin-binding globulin (CBG). These changes occur subsequent to the stress-induced rise in CORT. The following experiments examined whether exposure to an acute stressor (100 5-set inescapable tail shocks; IS) could also produce long term changes in basal CORT and CBG. We report that a single session of IS results in an increase in basal total serum CORT that persists 48-96 h after IS termination. The increase is present only at the diurnal trough (morning). CBG levels are also decreased for 24-48 h. The decrease is present at both the diurnal peak (evening) as well as the trough (morning). These changes result in an increase in the percent and amount of biologically active CORT (unbound or free). Thus, glucocorticoid-sensitive targets are exposed to high levels of free CORT for several days after IS termination. The long term increase in free CORT reported here may play an important role in mediating some of the effects produced by IS as well as those produced by other acute stressors. (Endocrinology 136: 5336-5342, 1995)
Journal Article•
TL;DR: In this paper, the effect of immune system stimulation and intracerebroventricular (i.c.v.) administration of interleukin-1 beta (IL-1 Beta) on hippocampal serotonergic neurotransmission, behavioral activity, and the hypothalamic-pituitary-adrenocortical (HPA) axis is described.
Abstract: In this study the effect of immune system stimulation and intracerebroventricular (i.c.v.) administration of interleukin-1 beta (IL-1 beta) on hippocampal serotonergic neurotransmission, behavioral activity, and the hypothalamic-pituitary-adrenocortical (HPA) axis is described. An in vivo microdialysis method was used to measure hippocampal extracellular concentrations of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in conscious, freely moving rats. In addition, we established a method to continuously monitor free corticosterone levels in dialysates. Behavioral activity was scored by measuring the time during which rats were active (locomotion, grooming, eating, drinking). We found a significant, positive relationship between behavioral activity and hippocampal extracellular concentrations of 5-HT. Intraperitoneal (i.p.) administration of the bacterial endotoxin lipopolysaccharide (LPS; 30, 100, and 300 micrograms/kg body weight) produced an increase in the extracellular concentrations of 5-HT and 5-HIAA in the hippocampus, which was paralleled by a significant decline in behavioral activity and a marked increase in extracellular corticosterone levels. Thus, the close correlation between hippocampal extracellular 5-HT levels and behavioral activity observed in control rats was disrupted in the LPS- treated animals. The effects of i.p. LPS could be mimicked by i.c.v. application of recombinant human IL-1 beta (hIL-1 beta; 100 ng). i.c.v. pretreatment with the IL-1 receptor antagonist (IL-1ra; 10 micrograms) antagonized the hIL-1 beta-induced effects. IL-1ra showed no intrinsic effects. Furthermore, it was found that i.c.v. pretreatment with IL-1ra (10 micrograms) significantly attenuated the i.p. LPS-induced (100 micrograms/kg body weight) rise in hippocampal extracellular 5-HT levels.
TL;DR: The close correlation between hippocampal extracellular 5-HT levels and behavioral activity observed in control rats was disrupted in the LPS- treated animals, and the effect of immune system stimulation and intracerebroventricular administration of interleukin-1 beta (IL-1beta) on hippocampal serotonergic neurotransmission, behavioral activity, andThe hypothalamic-pituitary-adrenocortical (HPA) axis is described.
Abstract: In this study the effect of immune system stimulation and intracerebroventricular (i.c.v.) administration of interleukin-1 beta (IL-1 beta) on hippocampal serotonergic neurotransmission, behavioral activity, and the hypothalamic-pituitary-adrenocortical (HPA) axis is described. An in vivo microdialysis method was used to measure hippocampal extracellular concentrations of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in conscious, freely moving rats. In addition, we established a method to continuously monitor free corticosterone levels in dialysates. Behavioral activity was scored by measuring the time during which rats were active (locomotion, grooming, eating, drinking). We found a significant, positive relationship between behavioral activity and hippocampal extracellular concentrations of 5-HT. Intraperitoneal (i.p.) administration of the bacterial endotoxin lipopolysaccharide (LPS; 30, 100, and 300 micrograms/kg body weight) produced an increase in the extracellular concentrations of 5-HT and 5-HIAA in the hippocampus, which was paralleled by a significant decline in behavioral activity and a marked increase in extracellular corticosterone levels. Thus, the close correlation between hippocampal extracellular 5-HT levels and behavioral activity observed in control rats was disrupted in the LPS-treated animals. The effects of i.p. LPS could be mimicked by i.c.v. application of recombinant human IL-1 beta (hIL-1 beta; 100 ng). i.c.v. pretreatment with the IL-1 receptor antagonist (IL-1ra; 10 micrograms) antagonized the hIL-1 beta-induced effects. IL-1ra showed no intrinsic effects. Furthermore, it was found that i.c.v. pretreatment with IL-1ra (10 micrograms) significantly attenuated the i.p. LPS-induced (100 micrograms/kg body weight) rise in hippocampal extracellular 5-HT levels.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: The results suggest that glucocorticoids modify sensitization of the behavioral effects of cocaine by acting on extracellular concentrations of dopamine, which may have implications for the development of new therapeutic strategies of addiction.
Abstract: Secretion of glucocorticoids seems to control stress-induced sensitization of the behavioral effects of drugs of abuse by acting on the mesencephalic dopaminergic transmission, the principal neural substrate of sensitization In order to investigate the mechanisms of this interaction between glucocorticoids and dopamine, we studied the sensitization of the increase in extracellular concentration of dopamine induced by cocaine in male rats in which corticosterone secretion was either intact or blocked Extracellular concentrations of dopamine were evaluated in the nucleus accumbens of freely moving animals by means of microdialysis Metyrapone, an inhibitor of corticosterone synthesis, was used to block stress-induced corticosterone secretion Food-restriction (90% of the initial body weight) was the stressor used to induce sensitization It was found that metyrapone (100 mg/kg sc twice a day for 8 d) suppressed stress- induced sensitization of the increase in accumbens dopamine induced by cocaine (10 mg/kg, ip) and sensitization of cocaine-induced locomotion Metyrapone suppressed both the development and the expression of sensitization Thus, sensitization was equally blocked when the metyrapone treatment started either 1 d before the start of food-restriction or 8 d later, that is, when food-restriction-induced sensitization to cocaine was already established In conclusion, our results suggest that glucocorticoids modify sensitization of the behavioral effects of cocaine by acting on extracellular concentrations of dopamine Since addictive properties of psychostimulants seem mediated by the increase in extracellular concentrations of dopamine they induce, these findings may have implications for the development of new therapeutic strategies of addiction
TL;DR: It is suggested that high concentrations of CORT or CRH synergistically decrease CRH-R messenger RNA (mRNA) levels in the AP, and that at least high CORT has an inhibitory effect on PVN CRh-R mRNA levels.
Abstract: Glucocorticoids and stress are known to influence the synthesis of corticotropin-releasing hormone (CRH) at a variety of sites in brain, including the hypothalamus and amygdala. The recent cloning of the CRH receptor (CRH-R) enabled us to determine whether glucocorticoids or stress influenced CRH action via regulation of CRH-R. We, therefore, used in situ hybridization to measure CRH-R messenger RNA (mRNA) levels in the hypothalamic paraventricular nucleus (PVN), anterior pituitary (AP), amygdala, and bed nucleus of the stria terminalis (BNST) under several conditions. Systemic corticosterone (CORT) treatment, both daily injection (5 mg/rat.day) up to 14 days and pellet implant (200 mg) for 14 days, decreased CRH-R mRNA in the PVN and lateral and basolateral nucleus of the amygdala (BLA). Corticosterone injection (10 mg/rat.day, for 7 days) decreased CRH-R mRNA in the AP. Adrenalectomy also decreased CRH-R mRNA in the PVN and AP, but did not alter it in the BLA. In both sham and adrenalectomized rats with...
TL;DR: A pivotal role for estrogens during early development for the determination of gender‐specific differences in HPA function in the mature animal is indicated and it is demonstrated for the first time that the brain‐organizing actions of gonadal steroids may extend to nonreproductive neuroendocrine axes.
Abstract: Estrogens, derived from the aromatization of testosterone in the brain, account for sex-specific organization of neural circuits controlling gonadotropin release and sexual behavior. This study examines the possible organizing role of perinatal gonadal steroids in the manifestation of known, albeit unexplained, male-female differences in basal and stress-related adrenocortical secretion. We document here the existence of gender-specific differences in the gene expression of hypothalamic corticotropin-releasing hormone (CRH), and hippocampal and hypothalamic glucocorticoid receptors (GR), diurnal corticosterone secretion, as well as in the responsiveness of CRH and GR mRNA levels to exogenous estradiol. In addition, we report that neonatal estrogenization of female rats profoundly affects several regulatory substrates of the hypothalamo-pituitary-adrenal (HPA) axis, namely, the gene expression of CRH, arginine-vasopressin (AVP) and GR in the brain, and the responsiveness of these parameters to estrogen. The neonatal treatment appeared to "defeminize" a number of neuroendocrine mechanisms related to HPA function; these changes were reminiscent of those observed in earlier studies on sexual differentiation of reproductive behavior and hormonal secretion. The results indicate a pivotal role for estrogens during early development for the determination of gender-specific differences in HPA function in the mature animal and demonstrate for the first time that the brain-organizing actions of gonadal steroids may extend to nonreproductive neuroendocrine axes.
TL;DR: This mechanism operates at physiological subnanomolar aldosterone concentrations and appears to be a likely candidate for rapid fine tuning of cardiovascular responsivity and may also contribute to known clinical features of mineralocorticoid action that are difficult to explain by the traditional genomic mechanism alone.
Abstract: Genomic mechanisms of steroid action have been increasingly elucidated over the past four decades. In contrast, rapid steroid actions have been widely recognized only recently, and detailed analysis of the mechanisms involved are still lacking. The present article describes rapid effects of mineralocorticoid hormones on free intracellular calcium in vascular smooth muscle cells as determined by fura 2 spectrofluorometry in single cultured cells from rat aorta. These effects are almost immediate and reach a plateau after only 3 to 5 minutes and are characterized by high specificity for mineralocorticoids versus glucocorticoids. The potent mineralocorticoids aldosterone and fludrocortisone are agonists with estimated apparent EC50 values of approximately 0.1 to 0.5 nmol/L; deoxycorticosterone acetate is an agonist with an EC50 of approximately 5 nmol/L; and progesterone, cortisol, corticosterone, and estradiol have much lower potency (EC50 values of approximately 0.5 to 5 mumol/L). The effect of aldosterone is blocked by neomycin and short-term treatment with phorbol esters but augmented by staurosporine, indicating an involvement of phospholipase C and protein kinase C. The Ca2+ effect appears to involve the release of intracellular Ca2+, as shown by the inhibitory effect of thapsigargin; intriguingly, a relatively small maximum effect (approximately 40 nmol/L increase) is consistently seen. This mechanism operates at physiological subnanomolar aldosterone concentrations and appears to be a likely candidate for rapid fine tuning of cardiovascular responsivity. It may also contribute to known clinical features of mineralocorticoid action that are difficult to explain by the traditional genomic mechanism alone.
TL;DR: The data support the notion that corticosterone exerts a concentration-dependent biphasic influence, via selective activation of hippocampal mineralocorticoid and glucocortioid receptor, on spatial memory and improve spatial memory in young and aged rats.
TL;DR: The involvement of the adrenal axis in the formation of partner preferences and the subsequent development of pair bonds provides a mechanism through which environmental and social factors may influence social organization in this species.
Abstract: Glucocorticoid levels in animals may respond to and influence the development of social attachments. This hypothesis was tested in prairie voles (Microtus ochrogaster), monogamous rodents that form long-term heterosexual pair bonds. In socially naive female prairie voles, cohabitation with an unfamiliar male resulted in a dramatic decline in serum corticosterone levels. When corticosterone levels were reduced via adrenalectomy, females developed partner preferences after 1 h of cohabitation, while sham-operated and untreated females required 3 h or more of nonsexual cohabitation to establish a partner preference. In adrenalectomized and intact females, exogenous injections of corticosterone, given prior to social exposure, prevented the development of preferences for the cohabitating male. Although corticosterone inhibited the development of partner preferences, it did not interfere with the expression of previously established social preferences. These results suggest that social stimuli can modulate adrenal activity and that adrenal activity, in turn, is capable of influencing the formation of adult social preferences in female prairie voles. The involvement of the adrenal axis in the formation of partner preferences and the subsequent development of pair bonds provides a mechanism through which environmental and social factors may influence social organization in this species.
TL;DR: Although a circadian variation in corticosterone was observed throughout, that in plasma I-ACTH was evident early in pregnancy but declined after midgestation, indicating marked changes in the hypothalamic-pituitary-adrenal axis during rat pregnancy and lactation.
Abstract: The circadian variation in immunoreactive (I-) ACTH and corticosterone was studied at several stages throughout rat pregnancy and compared with those before pregnancy and during lactation. Serial blood samples were obtained from chronically cannulated, conscious rats at 2- to 3-h intervals beginning at 0800 h at diestrus of the cycle; on days 2, 6, 10, 14, 18, and 22 of pregnancy (term = day 23); and on day 4 of lactation. Plasma I-ACTH and corticosterone were determined in all samples, and indices of their circadian variation (acrophase, mesor, and amplitude) were derived by cosinor analyses within each rat. A circadian variation in corticosterone was clearly evident in all groups, with individual cosinor r2 values being consistently high. Plasma I-ACTH also exhibited distinct circadian variation up to day 14 of pregnancy, but the cosinor r2 value then fell (P < 0.05, by analysis of variance) and remained low during lactation. Mesor levels (midpoint of the derived circadian range) of I-ACTH fell (P < 0.0...
TL;DR: It is concluded that transient activation of the HPA axis by a single administration of IL-1 beta induces a delayed and long-lasting hyperproduction, hyperstorage, and hypersecretion of AVP from hypothalamic CRH neurons that results in hyperresponsiveness of theHPA axis to subsequent stimuli.
Abstract: Hypothalamic CRH neurons that control ACTH secretion from the pituitary gland have secretory terminals in the external zone of the median eminence (ZEME). These neurons can coproduce vasopressin (AVP), a neuropeptide that potentiates the ACTH releasing effects of CRH. Recently, we found increased AVP production in adult rats weeks after single exposure to a stressor, which may play a role in event-induced stress disorders. Here, we describe the long-term changes in the HPA axis of adult male rats following a single exposure to a stressor, the cytokine interleukin-1 beta (IL-1 beta). The effects on storage and release of AVP and CRH were established by quantitative immunocytochemistry, the effects on ACTH and corticosterone responses by radioimmunoassay. Single administration of IL-1 beta (5 micrograms/kg i.p.) induces a delayed (at least 4 d) and a long-lasting (at least 3 weeks) increase of vasopressin (AVP) stores in CRH terminals of the ZEME without affecting the CRH stores, and a marked increase of the fraction of CRH terminals that costore AVP. Eleven days after IL-1 beta administration, a second IL-1 beta challenge causes a marked depletion of the AVP stores in the ZEME within 2 hr, which is not seen in rats treated with vehicle 11 d earlier. This is accompanied by twofold higher ACTH and corticosterone responses, as compared to those in vehicle pretreated rats. IL-1 beta-pretreated rats also showed increased ACTH and corticosterone responses to electric footshocks. We conclude that transient activation of the HPA axis by a single administration of IL-1 beta induces a delayed and long-lasting hyperproduction, hyperstorage, and hypersecretion of AVP from hypothalamic CRH neurons that results in hyperresponsiveness of the HPA axis to subsequent stimuli.
TL;DR: Evidence supports a previous suggestion that the activities of these two enzymes may be reduced in essential hypertension, but the contribution of these changes to hypertension is not known.
Abstract: We compared corticosteroid metabolite excretion rates and patterns in a group of 68 subjects with untreated essential hypertension and a matched group of 48 normotensive control subjects. The ratio of tetrahydrocortisol plus allotetrahydrocortisol to tetrahydrocortisone and the ratio of allotetrahydrocortisol to tetrahydrocortisol were significantly higher in the hypertensive group. This is qualitatively similar to the situation found in patients with the syndrome of apparent mineralocorticoid excess or subjects treated with licorice or carbenoxolone where hypertension is known to arise from deficiencies of 11β-hydroxysteroid dehydrogenase and 5β-reductase activities. The equivalent ratios for corticosterone metabolites were not different between groups, but total corticosterone metabolite excretion was higher in the hypertensive group. Plasma cortisol levels were lower in hypertensive than in control subjects, but corticosterone levels were higher. This evidence supports a previous suggestion that the activities of these two enzymes may be reduced in essential hypertension, but the contribution of these changes to hypertension is not known.
TL;DR: It is suggested that the shift in the central MR/GR balance of LEW rats, i.e. augmented MR-mediated effects of corticosterone, is the central regulating mechanism of the hyporeactive HPA axis in this rat strain.
TL;DR: The hypothesis that lactation‐induced changes in adrenal glucocorticoid and in circulating estrogen and progesterone levels would improve retention and/or acquisition of immobility in the Porsolt forced swim test was tested.
Abstract: Retention of immobility in the Porsolt forced swim test is believed to be dependent upon glucocorticoid secretion in male rats. Because lactating females exhibit increased basal glucocorticoid secretion and blunted stress responses, we tested the hypothesis that lactation-induced changes in adrenal glucocorticoid and in circulating estrogen and progesterone levels would improve retention and/or acquisition of immobility. Immobility was recorded during 3 intervals of 5 min on day 1 (acquisition) and one 5 min interval 24 h later (retention). Blood samples were collected before the swim test and at various times after the onset of stress for plasma ACTH and corticosterone (B) determinations. Male rats (young = 200 g, old = 325 g) were compared to virgin females (V) and to lactating females in early (day 8-10, EL) and late (day 17–19, LL) lactation. Adrenalectomy (ADX) and ovariectomy (OVX) were performed 5 and 10 days prior to testing, respectively.
All animals acquired immobility at the end of the 15 min swim on day 1, but only the young male group exhibited a significant retention of immobility on day 2. Total immobility was higher in males than females (V) although basal and stress-induced ACTH and B secretion were comparable on both testing days. Lactational status did not affect immobility in either the acquisition or retention phases. However, stress-induced ACTH secretion was greatly diminished in intact and ADX lactating females (EL and LL) compared to virgins (LL < EL < virgin), demonstrating a clear dissociation between behavioral and neuroendocrine responses. Following ADX, immobility in the retention phase was either decreased in males or increased in lactating females. Finally, OVX decreased immobility in both lactating (EL) and virgin females without significantly altering the magnitude of the ACTH and B responses to stress.
In summary, our results demonstrated both sex-related and lactation-related differences in the behavioral and endocrine responses to the forced swim test of Porsolt. Although retention of the immobile response is thought to involve glucocorticoids and/or opioids secreted during the first testing session, we did not find evidence for a direct relationship between basal or stress-induced total corticosterone secretion, the magnitude of ACTH response to stress and behavioral scores in the retention period. However, experimental variables such as body weight, sex and water depth could significantly modify the outcome of behavioral testing and question the validity of glucocorticoid-mediated retention processes. Since the effect of ADX was reversed in lactating females compared to male rats, we hypothesize that glucocorticoid sensitivity of cognitive processes controlling behavioral reactivity is different from that controlling hypothalamic-adrenocortical function. Our results also demonstrated a clear dissociation between behavioral and neuroendocrine responses to the swim test, in particular during lactation. In early and late lactation, blunted responsiveness to stress was not caused by enhanced glucocorticoid feedback but might result from modifications in the inhibitiory and/or stimulatory inputs to hypothalamic neurons controlling adrenocortical activity.