Showing papers on "Corticosterone published in 1990"
TL;DR: The changes in dendritic morphology observed may be indicative of neurons in the early stages of degeneration, as prolonged exposure to high levels of corticosterone has been shown by others to result in a loss of CA3 pyramidal cells.
1,010 citations
TL;DR: Histological analysis of a subset of aged animals showed that, while both AU and AI animals showed neuron loss in the pyramidal cell fields of the hippocampus, the loss was significantly greater in the AI animals, which showed clear evidence of increased HPA activity.
Abstract: There is a tendency for increased hypothalamic-pituitary-adrenal (HPA) activity with age in the rat, and the resulting elevations in circulating glucocorticoid levels have been implicated in the occurrence of hippocampal pathology and memory deficits. In the experiments reported here, we examined whether HPA dysfunction is selectively associated with cognitive impairments in a population of aged rats. Fifty-eight 23-27-month-old male Long-Evans rats were screened for spatial memory impairments using the Morris swim maze, and 2 groups of aged animals were selected; aged, cognitively impaired (AI) animals whose performance was significantly different (greater than 2 SD) from that of 6-month-old controls and aged, cognitively unimpaired (AU) animals whose performance was comparable to that of the young controls (a difference of less than 0.5 SD). Twenty-eight percent of the animals tested were designated as AI and 20% as AU. Histological analysis of a subset of these animals showed that, while both AU and AI animals showed neuron loss in the pyramidal cell fields of the hippocampus, the loss was significantly greater in the AI animals. The AI animals showed clear evidence of increased HPA activity. Thus, basal ACTH and corticosterone levels were significantly higher in the AI animals compared with both AU animals and young controls, especially during the dark phase of the cycle. The AI, AU, and young animals exhibited comparable corticosterone levels during a 20-min immobilization stress; however, following the termination of the stressor, corticosterone levels in AI animals were significantly elevated compared with both AU animals and controls.(ABSTRACT TRUNCATED AT 250 WORDS)
431 citations
TL;DR: Results show that dentate gyrus granule cells require glucocorticoids for their survival and for the maintenance of normal morphology and suggest that granule cell morphology and/or survival may undergo constant fluctuation in response to diurnal rhythms or stress-induced changes in glucOCorticoid levels.
348 citations
TL;DR: A classical action of glucocorticoids is to inhibit glucose uptake into various peripheral tissues, and two recent reports suggest that GCs do the same in the brain, but whether this inhibition occurred at the blood-brain barrier, and/or within neurons and glia themselves is unknown.
Abstract: A classical action of glucocorticoids (GCs) is to inhibit glucose uptake into various peripheral tissues. Two recent reports suggest that GCs do the same in the brain. Because of the in vivo nature of those studies, it was impossible to determine whether this inhibition occurred at the blood-brain barrier, and/or within neurons and glia themselves. In order to answer this and other mechanistic questions, we examined the effects of GCs on glucose transport in primary brain cultures. We established that uptake of 14C-2-deoxyglucose into hippocampal cultures was linear over a 15-min period and was inhibited by D-glucose and the uptake inhibitor cytochalasin B. Using this system, we found the following. (1) Both corticosterone and dexamethasone inhibited uptake into cultures containing both neurons and glia. (2) The effect was dose-dependent; steroid concentrations in the nanomolar range inhibited uptake from 20 to 33%. The effect was time-dependent, with more than 4 h of steroid exposure needed for inhibition. (3) Non-GC steroids did not inhibit uptake. (4) The GC inhibition seemed to be mediated by the type II (glucocorticoid) corticosteroid receptor. The effect was blocked by a type II, but not a type I (mineralocorticoid) receptor antagonist. Moreover, corticosterone inhibited only at concentrations well above the Kd for the type I receptor. Finally, aldosterone inhibited transport when applied at concentrations that bound heavily to type II receptors. (5) Corticosterone did not inhibit uptake in hypothalamic, cerebellar or cortical cultures, despite the presence of corticosteroid receptors in these cultures. (6) GCs inhibited uptake in both neuron- and glia-enriched hippocampal cultures.
344 citations
TL;DR: It is suggested that AS receptors in the brain, and especially the hippocampus, are more sensitive to circulating levels of glucocorticoids than the pituitary and there may be a greater capacity for physiological variations in type I receptor occupation in vivo than had previously been suggested.
247 citations
TL;DR: There is localized 11 beta-OHSD mRNA expression and enzyme bioactivity in rat brain, which corresponds to areas of reduced glucocorticoid or mineraloc Corticosterone receptor affinity for corticosterone, and may regulate the access of cortic testosterone to cerebral mineralocORTicoid and/or glucOCorticoids receptors and thus modulate corticosteroid effects on brain function.
Abstract: In peripheral aldosterone target sites (e.g., kidney), 11β-hydroxysteroid dehydrogenase (11β-OHSD) metabolizes corticosterone to inactive 11-dehydrocorticosterone and thus protects mineralocorticoid receptors from exposure to corticosterone in vivo. We have investigated whether 11β-OHSD could account for the site-specific differences in corticosteroid receptor sensitivity to corticosterone in rat brain. Enzyme activity, estimated as the percentage conversion of [3H]corticosterone to [3H] 11-dehydrocorticosterone in the presence of NADP+(200 μM), was: hippocampus, 55.8 ± 2.7%; cortex, 52 ± 3.1%; pituitary; 40 ± 2%, hypothalamus, 26.1 ± 1.2%; brain stem, 21.4 ± 1.7%; and spinal cord, 12.3 ± 1.8%. Northern blots, using [32P]dCTPlabeled probes from an llβ-OHSD cDNA clone derived from rat liver, showed expression of a single mRNA species in all brain areas, of identical size to 11β-OHSD mRNA in liver and kidney. Highest expression was found in hippocampus and cortex. In situ hybridization, using [35S]UTP-label...
235 citations
TL;DR: The striking difference between them is that unlike CGS 16949A, CGS 20267 does not affect adrenal steroidogenesis in vitro or in vivo, at concentrations and doses several orders of magnitude higher than those required to inhibit estrogen biosynthesis.
233 citations
TL;DR: It is reported that growth hormone secretion falls rapidly immediately upon separation of pups from the dam, while robust rises in corticosterone secretion are delayed for many hours, and growth hormone responses are observed earlier in ontogeny.
Abstract: Separation of neonatal rat pups from the dam have been reported to elicit two endocrine responses in the pup: a fall in growth hormone secretion and a rise in corticosterone secretion. However, the temporal, ontogenetic, and behavioral determinants of these responses have not been compared. In the present study, we report that these two responses can be differentiated on each of these criteria. Growth hormone secretion falls rapidly immediately upon separation of pups from the dam, while robust rises in corticosterone secretion are delayed for many hours. In addition, growth hormone responses are observed earlier in ontogeny. Finally, active maternal behavior is required for normal growth hormone secretion in 10-day-old rat pups, while passive sensory stimuli associated with the dam can significantly reduce the corticosterone response to separation.
229 citations
Journal Article•
TL;DR: It is shown that PVG rats that had been adrenalectomized developed severe disease from which they do not recover, and resistance to the induction of EAE could not be abrogated by adrenalectomy in all strains of rats studied.
Abstract: Experimental allergic encephalomyelitis (EAE) can be induced in some strains of rat but not others, by the injection of guinea-pig myelin basic protein in Freund's complete adjuvant. In the susceptible Lewis strain, spontaneous recovery from paralysis occurs and previous studies have shown that this recovery is dependent on the production, during the course of the disease, of high levels of corticosterone from the adrenal glands. Adrenalectomy completely abrogates the recovery phase and the disease becomes uniformly fatal unless steroid replacement therapy is given, which reproduces the serum levels of hormone that develop in intact animals with EAE. The PVG strain is not susceptible to EAE, but here it is shown that PVG rats that had been adrenalectomized developed severe disease from which they do not recover. As in the adrenalectomized Lewis rat, steroid replacement therapy could prevent the fatal outcome and in this case the disease course resembled that seen in intact Lewis animals. By a number of parameters PVG rats appear to make a more vigorous steroid response to stress than do Lewis. A comparison of the ratio of adrenal weight to body weight between these strains indicated that this ratio is larger in PVG, and serum corticosterone levels, in response to stress, were also found to be higher in this strain. Furthermore, basal levels of corticosterone were much more labile in PVG rats and had a higher mean value than those found in the age- and sex-matched Lewis animals with which they were compared. Genetic analysis using congenic rat strains showed that a high adrenal weight to body weight ratio was not linked to the major histocompatibility complex (MHC). It appears that the resistance to EAE of PVG rats depends on an enhanced stress response that mediates its immunosuppressive effect via the adrenal glands. While this stress response plays an essential part in the recovery of Lewis strain rats from EAE, it is sufficiently potent in PVG rats to virtually completely prevent signs of disease. Resistance to the induction of EAE could not be abrogated by adrenalectomy in all strains of rats studied. In particular, congenic PVG.RT1u rats, with the same background genes as PVG but with RT1u rather than the RT1cMHC genes of PVG, did not develop EAE when the adrenal glands were removed.(ABSTRACT TRUNCATED AT 400 WORDS)
205 citations
TL;DR: These MR and GR changes persist into senescence and have been proposed to result in altered CORT responsiveness, stress regulation, behavioural adaptation and brain aging.
204 citations
TL;DR: CRF receptors in the olfactory bulb were unchanged following acute or chronic restraint stress, consistent with previous observations that brain CRF receptors are neither changed by adrenalectomy, glucocorticoid administration, nor 18-48 h of continuous restraint stress.
TL;DR: The data indicate that MR and GR activations induce opposite actions on the spike accommodation/afterhyperpolarization of CA1 pyramidal neurons, an important intrinsic mechanism of these neurons to regulate their response to excitatory input.
Abstract: Pyramidal neurons in the rat hippocampus contain mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) to which the adrenal steroid corticosterone binds with differential affinity. We have used intracellular recording techniques to examine MR-mediated effects on membrane properties of CA1 pyramidal neurons in hippocampal slices from adrenalectomized rats. Low doses of corticosterone (1 nM) applied by perfusion for 20 min decreased the spike accommodation observed during a depolarizing current pulse (0.5 nA for 500 ms) and the amplitude of the subsequent afterhyperpolarization without affecting other membrane properties tested. The decrease became apparent ca. 15 min after steroid perfusion was started and reached its peak value 10-20 min after the steroid perfusion was terminated. The steroid effect was blocked by the MR antagonist spironolactone and mimicked by the natural MR ligand aldosterone (1 nM). Neurons recorded 30-90 min after termination of aldosterone application still displayed a decreased spike accommodation. However, 30-90 min after corticosterone application, the decrease in spike accommodation/afterhyperpolarization appeared to be reversed. Higher doses of corticosterone (greater than or equal to 30 nM) induced a significant increase in accommodation and amplitude of the afterhyperpolarization, as was previously observed for selective GR ligands. The data indicate that MR and GR activations induce opposite actions on the spike accommodation/afterhyperpolarization of CA1 pyramidal neurons, an important intrinsic mechanism of these neurons to regulate their response to excitatory input. We suggest that occupation of both MR and GR by the endogenous ligand corticosterone will result in an initial MR-mediated enhanced cellular excitability, which is gradually reversed and overridden by a GR-mediated suppression of cellular activity.
TL;DR: ACTH and corticosterone responses to 8-OH-DPAT, m-CPP, and DOI were examined in rats whose HPA axis had been suppressed by a single high dose injection of dexamethasone, suggesting that both of these 5-HT agonists may also act at the pituitary level to stimulate ACTH release in vivo.
Abstract: A substantial body of experimental evidence indicates that serotonin (5-HT) and several synthetic 5-HT receptor agonists activate the hypothalamic-pituitary-adrenal (HPA) axis. To explore the mechanism(s) by which 5-HT or 5-HT agonists enhance the activity of the HPA axis in vitro, we examined the stimulatory effects of the 5-HT1a agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), the 5-HT1c/5-HT1b agonist m-chlorophenylpiperazine (m-CPP), and the 5-HT2/5-HT1c agonist 1-(2,5-dimethoxy-4-iodophenyl)2-amino-propane (DOI) on plasma ACTH and corticosterone secretion in the rat. To test whether 8-OH-DPAT, m-CPP, or DOI increase plasma ACTH levels by stimulating the release of endogenous CRH, catheterized conscious male Sprague-Dawley rats were pretreated with hyperimmune CRH rabbit serum (TS-6) or normal rabbit serum and subsequently challenged with a maximally stimulatory dose of the above 5-HT agonists. Pretreatment with TS-6 completely suppressed the ACTH response to m-CPP and significantly blunted the responses to 8-OH-DPAT or DOI. To examine whether the remaining ACTH response to 8-OH-DPAT or DOI was also mediated by a pituitary site of action, we administered each of these agents to pituitary stalk-transected or sham-operated rats. The ACTH responses to 8-OH-DPAT and DOI in stalk-transected rats were preserved, although significantly blunted, compared to those in sham-operated rats. This suggested that both of these 5-HT agonists may also act at the pituitary level to stimulate ACTH release in vivo. Although the ACTH responses to 8-OH-DPAT, m-CPP, and DOI were blunted after both TS-6 pretreatment and pituitary stalk transection, corticosterone responses were only slightly affected, suggesting that some of these compounds may cause corticosterone release in the rat through another mechanism. To evaluate this hypothesis, ACTH and corticosterone responses to 8-OH-DPAT, m-CPP, and DOI were examined in rats whose HPA axis had been suppressed by a single high dose injection of dexamethasone. The corticosterone responses to 8-OH-DPAT and DOI were blunted compared to those of saline-pretreated rats, but were inappropriately high compared to the ACTH responses observed in these rats. On the other hand, both ACTH and corticosterone responses to m-CPP were completely abolished by dexamethasone.(ABSTRACT TRUNCATED AT 400 WORDS)
TL;DR: Neither steroid nor their combinations produced significant differences in daily urine volume or body weight gain compared with the CSF group, and the concomitant infusion of corticosterone antagonized the increase in blood pressure in a dose-dependent manner.
Abstract: There is evidence of crucial central nervous system involvement in the pathogenesis of mineralocorticoid-excess salt hypertension, as well as data indicating that corticosterone is the predominant ligand for the type I adrenocorticoid receptor in the brain. Miniosmotic pumps were used to deliver artificial cerebrospinal fluid (CSF), aldosterone (10 ng/h), corticosterone (10 or 20 ng/h), aldosterone (10 ng/h) plus corticosterone [10 ng/h intracerebroventricularly (icv)], or aldosterone (10 ng/h) plus corticosterone (20 ng/h icv). All animals were sensitized to mineralocorticoid hypertension by removing the right kidney and offering saline to drink. Indirect blood pressure by the unheated tail-cuff method and weights were measured twice weekly; 24-h urine volumes were measured once a week. The blood pressures of the four groups did not differ statistically before infusion. The blood pressures of those animals receiving CSF or corticosterone were not significantly elevated after 4-5 wk of intracerebroventricular infusion, whereas the aldosterone group had become significantly elevated within 2 wk. A similar study was done comparing the effects of intracerebroventricular infusion of aldosterone (10 ng/h), aldosterone (10 ng/h) and RU26988 (20 ng/h), and RU26988 (20 ng/h). RU26988, a selective type II receptor agonist, had no effect on the blood pressure, nor did it alter the pressor effect of intracerebroventricular aldosterone. The concomitant infusion of corticosterone antagonized the increase in blood pressure in a dose-dependent manner. Neither steroid nor their combinations produced significant differences in daily urine volume or body weight gain compared with the CSF group.
TL;DR: There was, however, adaptation of the HPA axis to the chronic ethanol treatment, and there were no signs of impaired negative feedback control of glucocorticoid secretion in the chronic-ethanol-treated rats.
Abstract: The ability of chronic ethanol stress to alter hypothalamic-pituitary-adrenal (HPA) axis function in a manner similar to that previously reported for other chronic stress treatments was evaluated. Inj
TL;DR: It appeared that the strain-specific corticoid increases ordinarily observed after acute shock were also evidence following a chronic stressor regimen, related to previously observed strain differences in stressor-induced alterations of brain norepinephrine, dopamine and serotonin.
Abstract: Exposure to acute inescapable footshock provoked marked increases of plasma corticosterone concentrations in six strains of mice (A/J, Balb/cByJ, C57BL/6J, C3H/HeJ, DBA/2J and CD-1). However, the magnitude of the increase, as well as the time required for corticosterone to return to control values, varied appreciably across strains. Moreover, it appeared that the strain-specific corticoid increases ordinarily observed after acute shock were also evidence following a chronic stressor regimen. The data were related to previously observed strain differences in stressor-induced alterations of brain norepinephrine, dopamine and serotonin, as well as variations in performance in several behavioral paradigms.
TL;DR: It is proposed that the increased HPA axis activity in obese rats and its resultant hypercorticism play a role in the establishment and maintenance of their syndrome.
Abstract: Adrenalectomy has been shown to reverse most facets of the syndrome of the genetically obese fa/fa rat. However, a detailed analysis of the hypothalamo-pituitary-adrenal (HPA) axis in these animals is lacking. In the present study, morning corticosteronemia was higher in obese rats of both sexes than in lean ones, whereas evening corticosteronemia was higher only in obese male rats. The HPA axis was further investigated using stressful stimuli. Immobilization, ether, and cold stresses resulted in greater corticosterone levels in obese than in lean animals. These abnormalities consisted in upward shifts of the corticosterone response in obese females and absolute increases in that of obese males, indicating that such alterations were more pronounced in obese male than obese female rats. Due to this, the putative origin of the increased corticosterone output of obese rats was studied in males. Greater levels of ACTH were reached in obese than in lean rats when submitted to a cold stress (6 C). Dexamethasone...
TL;DR: 5-HT increased type II, but not type I, corticosteroid receptor binding capacity in a dose-related manner, with the maximal effect observed at 10 nM 5-HT and no change in the affinity of the receptor for [3H]RU 28362.
Abstract: Previous work from our laboratory has shown that early postnatal handling of rat pups permanently increases hippocampal type II, but not type I, corticosteroid receptor binding. Handling also increases hippocampal 5-HT turnover, and the effect of handling on type II corticosteroid receptor binding is blocked by concurrent administration of the 5-HT2 receptor antagonist ketanserin. In view of these findings, the present studies examined the effects of 5-HT on type I ([3H]corticosterone) and type II ([3H]RU 28362) corticosteroid receptor binding in dispersed hippocampal cell cultures derived from animals killed at E19-20 in order to verify that 5-HT can act directly on hippocampal cells to alter corticosteroid receptor binding. Both type I and type II receptors were measurable in cultured hippocampal cells and the apparent affinity (Kd) for [3H]corticosterone (0.4 +/- 0.1 nM) and [3H]RU 28362 (0.8 +/- 0.1 nM) was similar to that from studies with intact animals. 5-HT increased type II, but not type I, corticosteroid receptor binding capacity in a dose-related manner, with the maximal effect (+188%) observed at 10 nM 5-HT and no change in the affinity of the receptor for [3H]RU 28362. The effect of 10 nM 5-HT on [3H]RU 28362 binding required a minimum of 4 d exposure and persisted for at least 7 d following the removal of 5-HT. The effect of 10 nM 5-HT on [3H]RU 28362 binding was completely blocked by the 5-HT2 receptor antagonists ketanserin and mianserin. There were no effects of the 5-HT1a antagonist, BMY 7378, or the 5-HT3 antagonist, MDL 72222.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal Article•
TL;DR: In this article, a 50-kDa polypeptide was identified as glial fibrillary acidic protein (GFAP) by hybrid selection and in vitro translation, and the 50 kDa protein was found to decrease in 5 brain regions after corticosterone (CORT) treatment.
TL;DR: It is suggested that endogenous brain CRF coordinates the suppressive effect of footshock stress on NK cytotoxicity independently of pituitary-adrenal activation.
Abstract: CRF acts within the brain to elicit changes in neuroendocrine, autonomic, and behavioral activity similar to that observed after stress. A reduction of splenic natural killer (NK) activity has also been described after the central administration of CRF. In this study we examined whether the central release of CRF plays a physiological role in mediating stressinduced suppression of NK cytotoxicity. Four sessions of footshock stress (1.5 mamp; 1-sec duration; 60-Hz sine wave; delivered randomly twice per min for 30 min) over a 48-h period significantly (P < 0.001) reduced splenic NK activity in the rat. Pretreatment of the animals by central administration of polyclonal CRF antibodies completely antagonized the stress-induced suppression of NK cell activity. In contrast, the peripheral immunoneutralization of CRF was ineffective. Measurement of circulating levels of ACTH and corticosterone demonstrated that stress-induced elevations of ACTH and corticosterone were significantly (P < 0.05) attenuated by peri...
TL;DR: The results suggest that both fast and delayed feedback corticosterone-inhibitory mechanisms may be blocked by relatively high levels of chronic stress or by chronic treatment with cortic testosterone, possibly as a consequence of decreased hippocampal glucocorticoid receptor number.
Abstract: A number of changes in anterior pituitary corticotrophs occur after chronic footshock. These include increased ACTH and β-endorphin content and a loss of glucocorticoid negative feedback on corticotro
Journal Article•
TL;DR: It is suggested that the sympathetic nervous system mediates the suppression of splenic NK cytotoxicity after i.c.v. CRF, and activation of the pituitary adrenal axis by CRF was dissociated from changes in NK activity.
Abstract: Corticotropin-releasing factor (CRF) acts within the brain to elicit changes in neuroendocrine, autonomic and behavioral activity similar to those observed after stress. A reduction of cellular immune function as measured by splenic natural killer cell activity has also been described following the central administration of CRF. In this study we evaluated the role of the sympathetic nervous system in mediating CRF-induced suppression of natural killer (NK) cytotoxicity. Synthetic rat CRF (1.0 microgram) microinjected into the lateral ventricle increased noradrenergic function and reduced NK activity in the rat spleen. Pretreatment of the animals by chemical sympathectomy (6-hydroxy-dopamine, 100 mg/kg i.p. daily over 10 days) produced a greater than 95% reduction of splenic norepinephrine concentration and abolished completely both the CRF-induced increase in plasma catecholamine levels and the reduction in splenic NK activity. In addition, beta adrenergic receptor blockade (either propranolol, 10 mg/kg i.p., or butoxamine, 25 mg/kg i.p. 30 min before i.c.v. infusion) antagonized the CRF-induced reduction in NK activity. Measurement of circulating levels of adrenocorticotrophic hormone and corticosterone demonstrated that activation of the pituitary adrenal axis by CRF was dissociated from changes in NK activity. These findings suggest that the sympathetic nervous system mediates the suppression of splenic NK cytotoxicity after i.c.v. CRF.
TL;DR: It is concluded that the changes in neuronal FLI correlate with demonstrated changes in neuroendocrine activity after ADX; however, suppression of ADX-induced FLI may require higher replacement levels of corticosterone than inhibition of ADx-induced ACTH secretion.
Abstract: To identify brain sites responding to the removal of corticosterone feedback by adrenalectomy (ADX), rat brains were processed for fos immunocytochemistry 1, 3, and 7 days after ADX, sham-ADX, or no surgery using a polyclonal antiserum to fos residues 132–154. Compared to SHAM, ADX rats exhibited strong fos-like immunoreactivity (FLI) only in the parvocellular neurons of the paraventricular hypothalamic nuclei (PVN) 1, 3, and 7 days after surgery. Replacement with a corticosterone pellet at the time of adrenalectomy (ADX + B) prevented this increase in PVN FLI in three of four rats at 1 day, all rats at 3 days, and two of seven rats 7 days after surgery; 100 μg/ml corticosterone in the drinking water for 2 days before perfusion reversed ADX-induced increases in PVN FLI in 7-day ADX rats. Providing 25 μg/ml corticosterone in the drinking water to ADX rats for 5 days after surgery did not prevent expression of PVN FLI, even though this dose has been shown to normalize morning basal ACTH levels in ADX rats. ...
TL;DR: The results indicate that GFAP mRNA is under negative regulation by glucocorticoids and suggests that glucocortsicoids may be used to inhibit GFAP gene expression in vivo in order to assess the role of GFAP in temporal aspects of central nervous system damage.
TL;DR: Pregnant exposure to EtOH during the second, but not the first or third week of gestation, alters the hypothalamic-pituitary-adrenal response to stress at 3 weeks of age, and a significant increase in CRF biosynthesis and expression, which may be at least in part a consequence of past elevated circulating corticosterone levels in EtOH-exposed dams, may modulate this augmented ACTH secretion in response to Stress.
TL;DR: Systolic blood pressure was measured, using an indirect tail method, in conscious male rats at several time intervals after the intracerebroventricular injection of mineraloand glucocorticoid agonists and antagonists.
Abstract: Systolic blood pressure was measured, using an indirect tail method, in conscious male rats at several time intervals after the intracerebroventricular injection of mineraloand glucocorticoid agonists and antagonists. Intracerebroventricular administration of the antimineralocorticoid RU 28318 (10 ng) decreased blood pressure, while the antiglucocorticoid RU 38486 (10 ng) caused an increase, which was slower in onset and of longer duration. The effect of the antimineralocorticoid was maximal at 8 h and had disappeared after 24 h. The antiglucocorticoid had a significant effect 24 and 48 h after injection. Neither antagonist was effective when administered sc at the same dose (10 ng). Intracerebroventricular administration of aldosterone (10 ng) and the selective glucocorticoid agonist RU 28362 (10 ng) increased and decreased blood pressure, respectively. Corticosterone given intracerebroventricullarly (10–100 ng) did not affect blood pressure unless the dose was increased to 1 ng. Two weeks after adrenale...
TL;DR: The findings show that the ligand binding specificity of canine MR and GR is remarkably different from that of rodent MR andGR, but is similar to that of recombinant-derived human receptors.
Abstract: A series of studies was started to gain insight into the functioning of the canine hypothalamo-pituitary-adrenocortical axis during normo- and hypercortisolemic states. In this first study, we have focused on the binding characteristics of the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) in the brain and pituitary of the adrenalectomized dog. In hippocampal cytosol at 0 C, corticosterone had the highest association rate, followed by cortisol and aldosterone. Cortisol had the most rapid rate of dissociation from MR at 0 C (t1/2 = 45.5 h), followed by aldosterone (70.4 h) and corticosterone (102 h). The selective glucocorticoid RU 28362 associated rapidly with hippocampal GR, attaining maximum binding within 4 h, and dissociated with a t1/2 of 34.8 h. Saturation binding of [3H]cortisol in adrenalectomized dog hippocampal cytosol produced a curvilinear Scatchard plot. After inclusion of RU 28362, [3H]cortisol bound solely to MR [dissociation constant (Kd) = 0.34 nM, Bmax = 72.8 fmol/mg]. GR capacity was determined with [3H]RU 28362 (Kd = 0.39 nM, Bmax = 120 fmol/mg). Competition binding analyses of various steroids for MR and GR revealed markedly different patterns of steroid binding specificity for these receptors. The rank order for displacement of [3H]aldosterone binding of MR was: corticosterone greater than aldosterone = cortisol greater than dexamethasone greater than ZK 91587 greater than RU 26752 greater than spironolactone much greater than RU 38486, and for displacement of [3H]RU 28362 binding of GR: RU 28362 much greater than corticosterone = cortisol greater than dexamethasone greater than aldosterone greater than ZK 91587 greater than RU 26752 = RU 38486 much greater than spironolactone. MR was located in all brain regions examined, with highest levels in the septo-hippocampal complex, whereas GR was rather evenly distributed. Substantial amounts of MR and GR were present in the anterior part of the pituitary as well as in the neurointermediate lobe. Our findings show that the ligand binding specificity of canine MR and GR is remarkably different from that of rodent MR and GR, but is similar to that of recombinant-derived human receptors. Spironolactone and RU 38486 are selective antagonists for MR and GR, respectively. In contrast to other species, the dog has relatively large quantities of MR widely distributed in the brain and pituitary, which makes this species an interesting animal model to study the role of corticosteroid receptor diversity in control of homeostasis.
TL;DR: The data indicate that fighting is not a generalized stressor and "Losing," in particular, appears to be an example of a biologically relevant stressor.
Journal Article•
TL;DR: In conclusion, alterations of HPA axis function occur during chronic mu or kappa opiate administration that are receptor-specific and involve multiple neural controls of the H PA axis.
Abstract: Chronic administration of opiates to rats results in HPA axis tolerance and abstinence-induced hypersecretion. The effects of specific mu and kappa tolerance and withdrawal on the functional secretion of the HPA axis were evaluated in this study. Adult male rats were injected s.c. twice daily with saline, morphine or U50,488 for 5 days. Serum adrenocorticotrophic hormone (ACTH) or corticosterone (CS) were determined by radioimmunoassay as measures of HPA axis function. Tolerance to morphine (10 mg/kg) and U50,488 (1 mg/kg), but no cross-tolerance, was observed suggesting the development of mu- or kappa-specific tolerance, respectively. Tolerance does not occur at the pituitary or adrenal levels after these paradigms because ACTH and CS responses to exogenous corticotropin-releasing factor and ACTH, respectively, were not attenuated. CS secretion in response to novelty stress was not affected by either chronic opiate treatment, but the circadian variation of CS levels was slightly blunted after chronic morphine. In contrast, the elevation of CS secretion by quipazine (0.5 mg/kg) and physostigmine (0.1 mg/kg) was attenuated after chronic U50,488, but not morphine administration. Both spontaneous and antagonist-precipitated withdrawal from morphine, but not U50,488, resulted in elevation of CS levels. Low doses of morphine suppressed morphine abstinence-induced CS hypersecretion, whereas, U50,488 and clonidine had no effect. In conclusion, alterations of HPA axis function occur during chronic mu or kappa opiate administration that are receptor-specific and involve multiple neural controls of the HPA axis.
TL;DR: The present studies suggest that this non‐selectivity includes the nuclear response element to which either MR or GR may bind to elicit a mineralocorticoid effect, and further underscore the importance of the enzyme 11SD in the specific mineralocortsicoid action of aldosterone.
Abstract: Patients with apparent mineralocorticoid excess (AME) have low or absent activity of the enzyme 11 beta OH steroid dehydrogenase (11SD), and inappropriately high intrarenal levels of cortisol resulting in Na+ retention and hypertension. Pseudohypoaldosteronism (PHA), in contrast, is characterized by salt wasting despite hyperaldosteronemia, reflecting low or absent mineralocorticoid receptors (MR). Although AME is presumed to reflect inappropriate cortisol occupancy of MR, several features also suggest inappropriate occupancy of glucocorticoid receptors (GR). To test this possibility, we administered carbenoxolone, which is known to block 11SD, to four patients with PHA, and observed marked mineralocorticoid effects, e.g., antinatriuresis and elevated plasma bicarbonate. To further test the possibility that occupancy of renal GR may induce a classical mineralocorticoid response, we administered the highly specific glucocorticoid RU 28362 to adrenalectomized rats and showed that it has profound antinatriuretic effects. Finally, by selectively blocking MR with RU 28318 or GR with RU 38486, we have shown that corticosterone, the physiologic glucocorticoid in rats, has an antinatriuretic effect in adrenalectomized rats via either MR or GR occupancy. Previous studies have clearly shown that MR are inherently nonselective and have equivalent intrinsic affinity for aldosterone, corticosterone, and cortisol. The present studies suggest that this nonselectivity includes the nuclear response element to which either MR or GR may bind to elicit a mineralocorticoid effect, and further underscore the importance of the enzyme 11SD in the specific mineralocorticoid action of aldosterone.