Biomedical subjects

J M Reul

Publications and source records attributed to J M Reul.

At least 55 records · Page 3Linked to original sources

PubMed1995

Do antidepressants stabilize mood through actions on the hypothalamic-pituitary-adrenocortical system?

Patients suffering from severe depression often show an increased activity of the hypothalamic-pituitary-adrenocortical (HPA) system, a premature escape from the cortisol suppressant action of dexamethasone, and a number of other neuroendocrine changes. This might be explained by defective glucocorticoid feedback inhibition. Normalization of the hyperactive HPA system occurs during successful antidepressant pharmacotherapy of depressive illness, and this could be achieved by antidepressant-induced increases in the cellular corticosteroid receptors, rendering the HPA system more susceptible to feedback inhibition by cortisol. Both mineralocorticoid- and glucocorticoid-receptor mRNA levels and hormone-binding activities are found to be increased following treatment of different cell lines or animals with antidepressants. Since the timecourse of antidepressant actions on corticosteroid receptors follows more closely that of clinical improvement of depression, antidepressants might elevate mood in depressives through their long-term effects on HPA regulation.

Affect↗

PubMed1995

Soluble interleukin-6 (IL-6) receptor augments central effects of IL-6 in vivo.

The pleiotropic cytokine interleukin-6 (IL-6) controls both the peripheral and central components of the acute-phase response. These activities are mediated via the IL-6 membrane receptor, but probably also via agonistic soluble IL-6 receptors (sIL-6Rs). In the present study we conducted dose-response experiments with rats that were intracerebroventricularly i.c.v.) injected with recombinant human IL-6 and sIL-6R and determined body temperature, locomotor activity, food intake, and water consumption using radiotelemetry and continuous recordings of feeding and drinking. IL-6 injected i.c.v. at 1, 10, and 100 ng increased body temperature and decreased locomotor activity and food intake, but it did not affect water consumption. When 10 ng sIL-6R, which lacked detectable biological activity, was injected i.c.v. 1 h before 1 ng IL-6, the central effects of IL-6 were enhanced and prolonged, and this was not due to endotoxin contamination of the recombinant proteins. Our data suggest that IL-6 plays an important role in the regulation of body temperature, general activity, and food intake in sick animals. Moreover, we have shown for the first time that it is possible to potentiate the effects of a mediator in vivo by administration of the corresponding receptor, which is a novel pharmacological tool for increasing receptor capacity.

Animals↗

PubMed1995

Long-term antidepressant treatment reduces behavioural deficits in transgenic mice with impaired glucocorticoid receptor function.

Impaired cognitive function and enhanced activity of the hypothalamic-pituitary-adrenocortical system are among the cardinal symptoms of major depression in humans that resolve after successful antidepressant treatment. We used a transgenic mouse model expressing antisense RNA complementary to that of glucocorticoid receptor (GR) mRNA to test the hypothesis that reduced GR function can cause these clinical disturbances. The transgenic mice show profound behavioural changes in a number of animal tests that are indicative of cognitive impairment. These mice also have elevated plasma corticotropin concentrations in response to stress. After long-term treatment with moclobemide, a reversible inhibitor of monoamine oxidase type A that acts clinically as an antidepressant, both the behavioural deficits and the hormonal alterations disappeared. These observations suggest that a transgenic mouse with GR dysfunction may be a useful model for investigation of drug effects on the cognitive and neuroendocrine aspects of depression.

Animals↗

PubMed1995

Long-term intracerebroventricular corticotropin-releasing hormone administration induces distinct changes in rat splenocyte activation and cytokine expression.

The effects of long-term corticotropin-releasing hormone (CRH) infusion in the lateral ventricle of the rat on hypothalamic-pituitary-adrenocortical (HPA) axis parameters and on the immune system function were studied. Compared with infusion of vehicle, the CRH treatment produced a sustained overactivity of the HPA axis, as evidenced by elevated plasma ACTH and corticosterone levels, increased anterior pituitary POMC messenger RNA (mRNA) expression, and adrenal enlargement. Long-term CRH treatment also inhibited body weight gain and reduced thymus and spleen weight. In the CRH-treated animals, both Concanavalin A (Con A)-induced T lymphocyte proliferation and lipopolysaccharide (LPS)-induced B lymphocyte mitogenesis was largely suppressed. Surprisingly, interleukin-2 (IL-2) levels were higher in supernatants of splenocyte cultures from CRH-treated rats than in those of control animals. However, IL-2 receptor alpha chain (IL-2R alpha) mRNA expression after Con A stimulation was highly suppressed in the CRH-treated animals. In addition, Northern blot analysis of RNA from splenocytes isolated from spleens of CRH-treated rats revealed a marked expression of IL-1 beta mRNA, in contrast to the barely detectable levels of this cytokine in control animals. Moreover, incubation of total splenocytes and spleen macrophages with LPS resulted in an enhanced induction of IL-1 beta mRNA in cells of CRH-treated rats compared with that of control animals. When adrenalectomized rats were treated with CRH or vehicle, the effects of the CRH treatment on T and B cell proliferation, IL-2 production, and IL-1 beta mRNA expression were abolished. Thus, a continuously increased HPA axis drive results in disparate changes in immune system function. Whether the observed changes in cytokine expression should be regarded as physiologically adaptive adjustments in support of immune function or as potentially pathological anomalies remains to be elucidated.

Animals↗

PubMed1995

Effect of bacterial endotoxin and interleukin-1 beta on hippocampal serotonergic neurotransmission, behavioral activity, and free corticosterone levels: an in vivo microdialysis study.

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)

Animals↗

PubMed1994

Heterodimerization between mineralocorticoid and glucocorticoid receptor: a new principle of glucocorticoid action in the CNS.

In the mammalian central nervous system, responsiveness to glucocorticoids is mediated by both the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). These pharmacologically distinct receptors are believed to bind to common response elements as homodimers. We provide evidence that MR and GR can form a heterodimeric complex with DNA-binding and transactivation properties different from those of the respective homodimers. There was a high degree of cooperativity of MR and GR in binding to a glucocorticoid response element. Transient transfection of a neuroblastoma cell line revealed a transcriptional response pattern of coexpressed MR and GR distinct from that obtained by MR or GR alone. Our findings demonstrate that heterodimerization of MR and GR is a hitherto unrecognized principle for the transcriptional regulation of glucocorticoid-responsive genes in tissue coexpressing these receptors.

Base Sequence↗

PubMed1994

Hypothalamic-pituitary-adrenocortical axis changes in the rat after long-term treatment with the reversible monoamine oxidase-A inhibitor moclobemide.

The effects of the reversible monoamine oxidaseA (MAOA) inhibitor moclobemide on the rat hypothalamic-pituitary-adrenocortical (HPA) axis were studied. The time-course experiments showed that moclobemide, given via the drinking water (4.5 mg/kg/day), produces significant decreases (p < 0.05) in adrenal weight after 5 (-23%) and 7 weeks (-16%) of treatment. It was found that long-term moclobemide treatment had neuroanatomically distinct effects on corticosteroid receptor expression. Hippocampal mineralocorticoid receptor (MR) levels were upregulated at 2 (+65%), 5 (+76%) and 7 (+19%) weeks of treatment. Glucocorticoid receptor (GR) levels in this limbic brain structure were slightly up-regulated by 10% at 5 weeks, and indistinguishable from controls after 2 and 7 weeks of treatment. After 5 weeks of treatment, MR levels were unchanged in the hypothalamus, and increased by 44, 24 and 28% in the neocortex, amygdala and anterior pituitary, respectively. GR concentrations were elevated by 24 and 14% in the hypothalamus and anterior pituitary, respectively, whereas neocortical and amygdaloid receptor levels were not altered. After 5 weeks of moclobemide treatment, marked decreases in [125I]Tyr0-ovine corticotropin-releasing hormone ([125I])-oCRH binding capacity and proopiomelanocortin (POMC) mRNA content were observed in the anterior pituitary. Regarding the functional implications of long-term anti-depressant treatment, moclobemide treatment (5 weeks, 4.5 mg/kg/day) significantly attenuated stress (30-min novel environment)-induced plasma ACTH (-35%) and corticosterone (-29%) levels; no changes were observed in basal plasma ACTH and corticosterone levels. In conclusion, this study shows that moclobemide has a concerted influence on multiple elements of the HPA axis manifesting functionally as a reduced neuroendocrine responsiveness to stress. In previous experiments, it was found that the structurally and pharmacologically distinct antidepressant amitriptyline after long-term administration also attenuated HPA axis activity. We postulate that an adjustement of HPA axis activity may be regarded as a common denominator for clinically efficacious antidepressant drugs.

Adrenal Cortex↗

PubMed1994

Prenatal immune challenge alters the hypothalamic-pituitary-adrenocortical axis in adult rats.

We investigated whether non-abortive maternal infections would compromise fetal brain development and alter hypothalamic-pituitary-adrenocortical (HPA) axis functioning when adult. To study putative teratogenic effects of a T cell-mediated immune response versus an endotoxic challenge, 10-d-pregnant rats received a single intraperitoneal injection of 5 x 10(8) human red blood cells (HRBC) or gram-negative bacterial endotoxin (Escherichia coli LPS: 30 micrograms/kg). The adult male progeny (3 mo old) of both experimental groups showed increased basal plasma corticosterone levels. In addition, after novelty stress the HRBC group, but not the LPS group, showed increased ACTH and corticosterone levels. Both groups showed substantial decreases in mineralocorticoid (MR) and glucocorticoid receptor (GR) levels in the hippocampus, a limbic brain structure critical for HPA axis regulation, whereas GR concentrations in the hypothalamus were unchanged and in anterior pituitary were slightly increased. HRBC and LPS indeed stimulated the maternal immune system as revealed by specific anti-HRBC antibody production and enhanced IL-1 beta mRNA expression in splenocytes, respectively. This study demonstrates that a T cell-mediated immune response as well as an endotoxic challenge during pregnancy can induce anomalies in HPA axis function in adulthood. Clinically, it may be postulated that disturbed fetal brain development due to prenatal immune challenge increases the vulnerability to develop mental illness involving inadequate responses to stress.

Animals↗

PubMed1994

Glucocorticoids suppress interleukin-1 receptor antagonist synthesis following induction by endotoxin.

Glucocorticoids, as part of their physiological role in the control of inflammatory and immune processes, suppress the expression of IL-1 and other cytokines. We have found a dose-dependent inhibition by dexamethasone (10 nM to 10 microM) of mRNA levels of the recently cloned IL-1 receptor antagonist (IL-1ra) in endotoxin-stimulated human monocytes. At the same concentrations, both dexamethasone and cortisol inhibited the secretion of IL-1ra. These inhibitory effects were reversed by blocking glucocorticoid receptors with the specific antagonist RU 38486, but not by adding exogenous IL-1, even up to 100 ng/ml, to the monocytes. A similar inhibition of IL-1ra mRNA and protein secretion was found in monocytes obtained after dexamethasone administration in vivo. In addition, we observed parallel increases in glucocorticoid and IL-1ra levels following endotoxin administration to normal volunteers. Our results show that glucocorticoids shut down not only IL-1 but also IL-1ra expression, ruling out induction of IL-1ra as part of the glucocorticoid antiinflammatory mechanism. The control of the delicate immunoregulatory balance of the IL-1/IL-1ra system during endotoxemia underscores the physiological importance of glucocorticoids in the final control of immune responses.

Adult↗

PubMed1994

Local administration of recombinant human interleukin-1 beta in the rat hippocampus increases serotonergic neurotransmission, hypothalamic-pituitary-adrenocortical axis activity, and body temperature.

In this study, we equipped rats with a microdialysis probe in the hippocampus, which enabled stress-free intrahippocampal administration of recombinant human IL-1 beta (hIL-1 beta). Perfusion of the probes was conducted with a Ringer's solution containing 0.1 or 1.0 microM hIL-1 beta or without hIL-1 beta, usually for 6 h. Time-dependent changes in serotonergic neurotransmission and hypothalamic-pituitary-adrenocortical activity were simultaneously monitored by measuring serotonin [5-hydroxytryptamine (5-HT)], 5-hydroxyindoleacetic acid, and corticosterone concentrations in the dialysates. In control rats, there was a clear relationship between extracellular 5-HT concentrations in the hippocampus and behavioral activity. Extracellular 5-HT levels were up to twice as high in behaviorally active rats compared to those in resting or sleeping animals. Intrahippocampal administration of hIL-1 beta markedly increased extracellular 5-HT concentrations in the hippocampus and induced a significant decrease in behavioral activity, thereby uncoupling the parallelism between changes in 5-HT and changes in behavioral activity observed in control rats. Perfusion with 0.1 microM hIL-1 beta, but not with 1 microM hIL-1 beta, produced a decrease in 5-hydroxyindoleacetic acid levels, followed by a return to preinfusion levels. Moreover, intrahippocampal administration of hIL-1 beta increased hypothalamic-pituitary-adrenocortical axis activity, as evidenced by marked increases in both plasma ACTH and plasma and dialysate corticosterone levels. In addition, a rise in body temperature by approximately 2 C was observed at time points at which the effects of hIL-1 beta on 5-HT and corticosterone levels were (near-)maximal. hIL-1 beta-treated rats displayed typical characteristics of sickness behavior, such as immobility, piloerection, and a curled-up body posture. Most importantly, no effects were found either with heat-inactivated hIL-1 beta or when hIL-1 beta was administered via a probe implanted in the neocortex. Based on these results, we postulate that the hippocampal IL-1 system may play an important role in the coordination of neuroendocrine, autonomic, and behavioral responses after an immune challenge.

Adrenal Cortex↗

PubMed1994

Enhancement of rat splenic lymphocyte mitogenesis after short term preexposure to corticosteroids in vitro.

Numerous previous studies investigating the effects of corticosteroids on immune proliferation reported almost unanimously inhibitory effects. However, in many of these studies, high concentrations of corticosteroids (micromolar range) and long incubation times (days) were used. We have investigated whether corticosteroid hormones at low physiological (nanomolar) vs. high (micromolar) concentrations have distinct effects on immune cells after short term (minutes) as opposed to long term preexposure (hours). When rat splenocytes were preincubated with high concentrations (0.1-1 microM) of corticosterone (CORT) or with the specific glucocorticoid agonist RU 28362 (0.1 microM) for 1-6 h, washed, and then exposed to the T-cell mitogen Concanavalin-A, a time- and dose-dependent inhibition of lymphocyte mitogenesis over the next 3 days of culture was found. Preincubation with the glucocorticoid antagonist RU 486 completely blocked this inhibitory effect of CORT and RU 28362. Preexposure of splenocytes to CORT for 10-60 min did not alter mitogenesis. No differences were observed between intact and adrenalectomized (ADX) rats. However, if splenocytes from ADX rats were used in the presence of the glucocorticoid antagonist RU 486, the proliferative response over a 3-day period was stimulated by short term preexposure (10-30 min) to low concentrations (3-30 nM) of CORT. Under these incubation conditions, the mineralocorticoid aldosterone, in the presence of RU 486; also produced a stimulatory effect on ADX splenic lymphocyte mitogenesis, whereas RU 28362 was not effective. Corticosteroid receptor binding studies revealed the presence of mineralocorticoid (MR) as well as glucocorticoid (GR) receptors (45 and 600 fmol/mg protein, respectively) in the spleen. In conclusion, low physiological concentrations of CORT and aldosterone have novel stimulatory properties on mitogenesis of splenic lymphocytes from ADX rats. These effects become evident in the presence of GR antagonist and persist after short corticosteroid preexposure times. In contrast, after prolonged preincubation with high concentrations of corticosteroids, the well known immunosuppressive action is observed. We postulate that distinct MR- and GR-mediated effects may underlie these differential steroid actions on splenic lymphocyte proliferation.

Adrenal Cortex Hormones↗

PubMed1994

The role of the hypothalamic-pituitary-adrenocortical system during inflammatory conditions.

Infections and injury are often accompanied by the production of large quantities of proinflammatory mediators such as cytokines and eicosanoids. These substances have been shown to efficiently activate the hypothalamic-pituitary-adrenocortical (HPA) system. The glucocorticoid hormones secreted from the adrenal cortex seem to be crucial for survival because they have an inhibitory influence on inflammatory processes, which, if uncontrolled, may become toxic for the host. Furthermore, these steroid hormones are known to support thermogenesis by inducing or repressing key enzymes of carbohydrate, lipid, and protein metabolism, and thus may also facilitate energy mobilization during fever, which usually accompanies infectious diseases. Finally, a number of studies suggest that glucocorticoids attenuate debilitating symptoms of inflammatory mediators, such as sleepiness, loss of appetite, and suppression of reproductive functions. One can assume that glucocorticoids exert similar behavioral effects during inflammatory conditions, which are seen in infectious diseases. Corticotropin-releasing hormone (CRH), the major hypothalamic component of the HPA system, is a putative mediator of the central effects of cytokines and autacoids because it inhibits growth, reproduction, and food intake. In contrast, CRH decreases sleep duration. Vasopressin, another hypothalamic peptide of the HPA system, counteracts fever and sickness behavior and is thought to support recovery from inflammatory diseases. Apparently, a well-balanced, concerted action of proinflammatory mediators, glucocorticoids, and hypothalamic peptide hormones provides not only an efficient principle for combating microorganisms and support of tissue repair but also for self-protection of the host during the stress of inflammation. Therefore, an impairment of the HPA system under inflammatory conditions often has severe pathological consequences, for example, in patients suffering from Addision's disease and arthritis.

Animals↗

PubMed1993

Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands.

We characterized the pharmacological profiles of the human mineralocorticoid and glucocorticoid receptor for 11 natural and synthetic steroids regarding binding pharmacology, intracellular localization of hormone-receptor complexes, and agonistic or antagonistic properties at the gene expression level. The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. These results are supported by immunofluorescence studies, in which both unliganded human mineralocorticoid and glucocorticoid receptors were distributed throughout the cytoplasm and nucleus, whereas agonist- as well as antagonist-receptor complexes showed an exclusively nuclear localization. These results contribute to the understanding of antihormone pharmacology and increase our understanding of the role of human mineralocorticoid and glucocorticoid receptors in physiological processes during different endocrine states.

Aldosterone↗

PubMed1993

Glucocorticoid and mineralocorticoid receptors in rat neocortical and hippocampal brain cells in culture: characterization and regulatory studies.

Glucocorticoid and mineralocorticoid binding sites were characterized in cell cultures derived from neocortical and hippocampal brain tissue from fetal (E18) rats. Specific and saturable binding was detected in living cells with a sensitive whole cell binding method using [3H]dexamethasone ([3H]DEX) and [3H]aldosterone ([3H]ALDO) (in the presence of RU 28362, a selective glucocorticoid receptor (GR) agonist) as ligands for the measurement of glucocorticoid and mineralocorticoid receptors (MRs), respectively. Specific corticosteroid binding was demonstrated as early as day 4 in culture in neocortical cells, with a time-dependent increase in binding sites during further culturing time. At 7-9 days in vitro, Scatchard analysis of [3H]DEX binding revealed a maximum binding capacity (Bmax) of 83.4 +/- 5.0 fmol/mg protein and a binding affinity (Kd) of 3.6 +/- 0.4 nM in neocortical brain cells. Competition binding studies with [3H]DEX demonstrated a glucocorticoid specificity of receptor sites (relative binding affinity: RU 28362 = DEX > PROG > ALDO). Similar binding characteristics were demonstrated for GRs in cultures derived from fetal hippocampal tissue (Bmax 49.1 +/- 5.8 fmol/mg protein, Kd 3.5 +/- 0.2 nM). Analysis of MRs with [3H]ALDO (+RU 28362) revealed specific and saturable binding in hippocampal cultures, with a Bmax of 8.0 +/- 0.5 fmol/mg protein and a Kd of 0.2 +/- 0.1 nM. Competition studies with [3H]ALDO showed a mineralocorticoid-like pattern of receptor binding (relative binding affinity: CORT = ALDO > PROG > DEX). In addition, small numbers of MRs were detectable in cortex-derived cultures (Bmax: 3.7 +/- 0.8 fmol/mg protein, Kd: 0.3 +/- 0.2 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗

PubMed1993

Progesterone receptor-mediated effects of neuroactive steroids.

Several 3 alpha-hydroxysteroids accumulate in the brain after local synthesis or after metabolization of steroids that are provided by the adrenals. The 3 alpha-hydroxy ring A-reduced pregnane steroids allopregnanolone and tetrahydrodeoxycorticosterone are believed not to interact with intracellular receptors, but enhance GABA-mediated chloride currents. The present study shows that these neuroactive steroids can regulate gene expression via the progesterone receptor. The induction of DNA binding and transcriptional activation of the progesterone receptor requires intracellular oxidation of the neuroactive steroids into progesterone receptor active 5 alpha-pregnane steroids. Thus, at physiological concentrations, these neuroactive steroids regulate neuronal function through their effects on both transmitter-gated ion channels and steroid receptor-regulated gene expression.

Base Sequence↗

PubMed1993

Differential effects of corticosteroids on rat peripheral blood T-lymphocyte mitogenesis in vivo and in vitro.

The effects of corticosteroids were studied on the concanavalin A (Con A)-induced mitogenesis of peripheral blood T-lymphocytes obtained from intact and adrenalectomized (ADX) Wistar rats. One week of adrenalectomy reduced the proliferative response of T-cells by 65% compared with sham-operated controls. Substitution of ADX rats with subcutaneously implanted 12.5-mg corticosterone (Cort) pellets, which resulted in low circulating Cort levels (17 +/- 3 nM), restored the reduced proliferative capacity to that of sham-ADX animals. In contrast, T-lymphocyte proliferation was nearly absent in ADX rats substituted with high circulating Cort levels (173 +/- 15 nM; 100-mg Cort pellet). In vitro, Cort suppressed the mitogenic response of T-lymphocytes from ADX and sham-ADX animals. The glucocorticoid antagonist RU-486 (500 nM) completely blocked this suppressive effect. However, a 10 times lower concentration of RU-486 reversed the effects of a low (10 nM) Cort concentration from suppression to stimulation. It is concluded that high Cort concentrations in vivo and in vitro suppressed T-lymphocyte mitogenesis but that low concentrations in vivo were stimulatory, whereas this stimulation in vitro occurred only in the presence of antiglucocorticoids. These opposing effects of Cort emphasize a bimodal regulatory role of this hormone in immune regulation that may be mediated by different corticosteroid receptors.

Adrenalectomy↗

PubMed1993

Increased neuroendocrine reactivity and decreased brain mineralocorticoid receptor-binding capacity in aged dogs.

The effects of aging on the regulation of the hypothalamus-pituitary-adrenocortical (HPA) system of the dog were investigated. For this purpose, we compared 11 healthy dogs, 11-14 yr old, with 14 young mature dogs, 18-24 months of age. Significantly higher basal HPA activity in the old dogs was indicated by their higher resting plasma concentrations of ACTH, alpha MSH, and cortisol over a 6-week period and higher cortisol excretion in 24-h urine. After stress by immobilization as well as by light electric foot shocks and after i.v. administration of 1 microgram/kg CRH, the old dogs had higher peak levels of ACTH and cortisol, but not of alpha MSH. The areas under the curve, corrected for the basal levels, for ACTH and cortisol after these challenges were also greater in the old dogs. The half-times to reach a 50% increment and a 50% decrement in the time-concentration curves of ACTH and cortisol were similar in old and young dogs. There were no differences between the old and young dogs in their response to i.v. administration of 0.01 mg/kg dexamethasone. The clearance of [14C]cortisol from plasma, as calculated in a two-compartment model, was significantly reduced in aged dogs. In the old dogs, the stress- and CRH-induced cortisol peaks were relatively higher than those of ACTH, and their adrenals weighed significantly more, suggesting chronic hyperadrenocorticotropism. Aging had a markedly different effect on the two types of corticosteroid receptors in brain and pituitary. The binding capacity of type II or glucocorticoid receptors (GRs) in the old dogs was unchanged compared with that in the young dogs in all investigated brain structures except the anterior pituitary, in which the number of GRs was increased up to 170%. Type I or mineralocorticoid receptor (MR)-binding capacity was largely decreased in the brain of old dogs. The MR levels in old dogs, expressed as a percentage of the corresponding levels in young dogs, were 34% in the dorsal hippocampus, 58% in the ventral hippocampus, 37% in the septum, and 54% in the hypothalamus. In the anterior pituitary, MR capacity was unchanged. There was no difference between Kd values of MR and GR binding in young and old dogs. We conclude that these aged dogs had elevated basal HPA activity, characterized by increased levels of basal ACTH and cortisol in plasma and of urinary cortisol excretion and by hyperreactivity of ACTH and cortisol secretion in response to challenge by stress or CRH.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex↗

PubMed1993

Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system.

The effects of the tricyclic antidepressant amitriptyline on the rat hypothalamic-pituitary-adrenocortical (HPA) system were studied. The time-course experiments showed that amitriptyline, given via the drinking water (4.5 mg/kg.day), produces significant decreases (P < 0.05) in adrenal weight after 5 (-20%) and 7 weeks (-21%) of treatment. Hippocampal mineralocorticoid receptor (MR) levels were down-regulated at days 3 (-27%) and 7 (-20%), and transiently up-regulated at 2 (+40%), 5 (+74%), and 7 (+18%) weeks of treatment. Hippocampal glucocorticoid receptor (GR) levels were slightly down-regulated at days 3 (-8%) and 7 (-17%), transiently up-regulated by 26% at 5 weeks, and indistinguishable from controls after 7 weeks of treatment. MR levels were unchanged in the hypothalamus and neocortex, whereas hypothalamic GR concentrations were elevated and neocortical receptor levels were not altered. Dose-response experiments showed significant decreases in adrenal weight when rats were treated with 4.5 (-14%), 8.8 (-16%) and 14.5 (-13%) mg/kg.day antidepressant, but this applied only for the 4.5- (-14%) and 8.8- (-12%) mg/kg.day doses when the ratio of adrenal weight to body weight was considered. The dose-response relationship regarding hippocampal GR content displayed an inverted U-shaped curve, whereas this was less marked for MR levels. A dose of 4.5 mg/kg.day appeared to be optimal for the rise in MR as well as GR. Concerning the neuroendocrine implications of chronic antidepressant treatment, amitriptyline (5 weeks, 4.5 mg/kg.day) produced significant decreases in basal (ACTH, -47%; corticosterone, -31%) as well as stress (30 min novel environment)-induced plasma ACTH (-38%) and corticosterone (-57%) levels. Previous experiments have forwarded a role of limbic MR in the tonic control of basal HPA activity. Based on the present data, we hypothesize that during amitriptyline treatment a rise in limbic MR may be the initial phenomenon in a successively adjusting HPA system, as evidenced by the decreasing plasma hormone concentrations, declining adrenal size, and up-regulation of GR in particular brain regions.

Adrenal Cortex↗