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Biomedical subjects

J M Reul

Publications and source records attributed to J M Reul.

At least 37 records · Page 2Linked to original sources
PubMed1998

Altered neuroimmunoendocrine communication during a condition of chronically increased brain corticotropin-releasing hormone drive.

Presently, it is clear that the brain, immune system, and endocrine system build a complex network of interactions at various levels. Inflammation, which may be regarded as a stressful challenge, initiates apart from immunological, autonomic, and neuroendocrine responses also profound behavioral (e.g., immobility, social disinterest) changes. Key mediators herein are corticotropin-releasing hormone (CRH) and cytokines, such as interleukin-1 beta (IL-1 beta). Currently, the behavioral changes, collectively termed sickness behavior, are thought to be adaptive responses to support the body's efforts to fight the infection. Using in vivo microdialysis and biotelemetry in freely moving animals, we have studied the monoaminergic circuits in the brain implicated in the regulation of physiological and behavioral responses to a peripheral inflammatory challenge (see also chapter of Linthorst and Reul in this volume). To expand our insight into the relationship between hypersecretion of CRH and physiological and behavioral abnormalities associated with stress-related disorders, a series of experiments was conducted with long-term centrally CRH-infused rats. These rats showed reduced body weight gain, decreased food intake, elevated plasma ACTH and corticosterone levels, thymus involution and immunosuppression, but, paradoxically, enhanced IL-1 beta mRNA expression in spleen macrophages. After a peripheral endotoxic challenge on the seventh day of treatment, the CRH-infused rats produced aberrant (i.e., blunted and/or delayed) HPA axis, fever, behavioral, and hippocampal serotonergic responses. However, endotoxin-induced plasma IL-1 and IL-6 bioactivities were significantly enhanced in these animals. The data show that chronically elevated central CRH levels as occurring during chronic stress result in defective central nervous system and immune system responses to an acute (inflammatory) challenge. These observations provide evidence that chronic CRH hypersecretion is an important factor in the etiology of stress-related disorders.

Animals↗
PubMed1998

Induction of cytokine receptors by glucocorticoids: functional and pathological significance.

Current concepts on the role of glucocorticoid hormones in the regulation of inflammatory and immune responses depict this role as being inhibitory. Over the past decade, however, a large variety of studies have shown that glucocorticoids also exert stimulatory effects on immune function, suggesting that the present concept of the role of glucocorticoids in the immune system in not sufficient and needs to be extended. Here, Jan Wiegers and Hans Reul ask how these apparently paradoxical effects fit together and what their functional and pathological significance might be.

Animals↗
PubMed1998

Behavioral, physiological, and neuroendocrine stress responses and differential sensitivity to diazepam in two Wistar rat lines selectively bred for high- and low-anxiety-related behavior.

Two Wistar rat lines, selectively bred for high-anxiety-related behavior (HAB) and low-anxiety-related behavior (LAB) in the elevated plus-maze test, were tested for the susceptibility of their behavioral characteristics to anxiolytic treatment and for their endocrine and physiological reactivity to different stressors. Injection of 1 mg/kg diazepam failed to affect line differences in coping strategy but resulted in a marked (20-fold) decrease in plus-maze anxiety in HAB rats; whereas, the anxiolytic effect was less pronounced in LAB animals. Biotelemetrical measurements revealed that HAB and LAB rats do not significantly differ in their baseline body temperature, locomotor activity, food and water intake, or in stress-induced alterations of the diurnal rhythms in these parameters. However, line differences were found in acute changes in body temperature and locomotor activity following stress exposure, LAB rats responding with a greater, albeit shorter, increase in body temperature and activity than HAB animals. Basal ACTH and corticosterone plasma levels as well as pituitary reactivity to intravenously administered CRH (40 ng/kg) were similar in both lines, although, especially in response to plus-maze exposure, HAB rats tended toward higher ACTH secretion than LAB rats. These data confirm that animals with high or low basal levels of anxiety may be a promising model for studying the mechanisms of action of anxiolytic substances. Nevertheless, the endocrine findings support the notion that the reactivity of the hypothalamo-pituitary-adrenocortical system and anxiety-related behavior can be regulated independently.

Adrenocorticotropic Hormone↗
PubMed1998

Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1.

Corticotropin-releasing hormone (CRH) is a potent mediator of endocrine, autonomic, behavioural and immune responses to stress, and has been implicated in the stress-like and other aversive consequences of drug abuse, such as withdrawal from alcohol. Two CRH receptors, Crhr1 and Crhr2, have been identified in the mouse. Crhr1 is highly expressed in the anterior pituitary, neocortex, hippocampus, amygdala and cerebellum, and activation of this receptor stimulates adenylate cyclase. Here we show that in mice lacking Crhr1, the medulla of the adrenal gland is atrophied and stress-induced release of adrenocorticotropic hormone (ACTH) and corticosterone is reduced. The homozygous mutants exhibit increased exploratory activity and reduced anxiety-related behaviour under both basal conditions and following alcohol withdrawal. Our results demonstrate a key role of the Crhr1 receptor in mediating the stress response and anxiety-related behaviour.

Adrenocorticotropic Hormone↗
PubMed1998

Tumour necrosis factor-alpha and interleukin-2 differentially affect hippocampal serotonergic neurotransmission, behavioural activity, body temperature and hypothalamic-pituitary-adrenocortical axis activity in the rat.

Intraperitoneal endotoxin injection and central administration of interleukin (IL)-1beta profoundly activate hippocampal serotonergic neurotransmission. This study was designed to investigate, using in vivo microdialysis, the effects of another endotoxin-induced proinflammatory cytokine, tumour necrosis factor-alpha, and the effects of the non-inflammatory cytokine, IL-2, on hippocampal extracellular levels of serotonin. To compare the effects of these cytokines on neurotransmission with the effects on physiological parameters and behaviour, hypothalamic-pituitary-adrenocortical (HPA) axis activity, body temperature and behavioural activity were monitored as well. Time-dependent changes in serotonergic neurotransmission and HPA axis activity were determined by measuring serotonin, its metabolite 5-hydroxyindoleacetic acid and free corticosterone in dialysates. Total behavioural activity was scored by assessing the time during which rats were active. Core body temperature was measured by biotelemetry. Intracerebroventricular injection of 50 or 100 ng recombinant murine tumour necrosis factor-alpha exerted no effect on hippocampal serotonergic neurotransmission, and induced no signs of sickness behaviour. However, these doses produced a dose-dependent increase in body temperature and free corticosterone levels. In contrast, intracerebroventricular administration of 500 ng, but not of 50 ng, recombinant human IL-2 produced a marked increase in hippocampal extracellular concentrations of serotonin and 5-hydroxyindoleacetic acid, accompanied by a pronounced behavioural inhibition and other signs of sickness. Moreover, both doses of IL-2 caused a dose-dependent increase in body temperature and free corticosterone levels. Interestingly, intracerebroventricular pretreatment with the IL-1 receptor antagonist showed that the effects of IL-2 on hippocampal serotonin were completely dependent on endogenous brain IL-1. However, IL-1 seemed to play only a minor role in the IL-2-induced increase in free corticosterone. Taken together, the results show that cytokines produce partially overlapping brain-mediated responses, but are selectively effective in stimulating hippocampal serotonergic neurotransmission and inducing sickness behaviour. Moreover, we postulate that activation of hippocampal serotonin release is instrumental in the full development of behavioural inhibition.

Animals↗
PubMed1997

Centrally administered oligodeoxynucleotides in rats: occurrence of non-specific effects.

We studied the effects of various intracerebroventricularly administered oligodeoxynucleotides on body temperature, locomotor activity, food intake and water consumption in rats during a 24 h period with a radio-telemetric system. Both complete phosphorothioate oligodeoxynucleotides and end-inverted oligodeoxynucleotides dose-dependently elevated body temperature, suppressed food and fluid intake and inhibited nighttime activity. Apparently these effects do not depend on the nucleotide sequence because antisense and sense arginine vasopressin and oxytocin oligodeoxynucleotides, as well as a missense oligodeoxynucleotide produced comparable changes in the autonomous and behavioral parameters. In control experiments neither contaminants from the chemical synthesis nor endotoxins produced such effects, whereas native DNA from salmon sperm did. Fever and sickness-like behavior in response to missense phosphorothioate oligodeoxynucleotides were accompanied by elevated concentrations of circulating corticosterone and by a marked increase in interleukin 6 mRNA in brain and spleen, indicating that centrally administered oligodeoxynucleotides stimulate the production of pyrogenic inflammatory mediators in both central nervous system and peripheral tissues. Our results indicate that centrally administered oligodeoxynucleotides produce beside their intended sequence-specific effects also transient and sequence-independent effects due to their nucleic acid structure.

Animals↗
PubMed1997

Long-term intracerebroventricular infusion of corticotropin-releasing hormone alters neuroendocrine, neurochemical, autonomic, behavioral, and cytokine responses to a systemic inflammatory challenge.

Corticotropin-releasing hormone (CRH) was infused intracerebroventricularly into rats for 7 d via a miniosmotic pump (1 microg . microl-1 . hr-1). Body temperature and locomotor activity were recorded during the treatment using biotelemetry, whereas hippocampal serotonergic neurotransmission and free corticosterone levels were monitored using in vivo microdialysis on day 7 of CRH treatment. During the microdialysis experiment, behavioral activity was scored by assessing the time during which rats were active (locomotion, grooming, eating, drinking). Continuous intracerebroventricular infusion of CRH produced a transient increase in body temperature and locomotion. Moreover, intracerebroventricularly CRH-treated rats showed elevated free corticosterone levels with no apparent diurnal rhythm. Intraperitoneal administration of bacterial endotoxin -lipopolysaccharide (LPS); 100 microg/kg body weight- on day 7 of CRH/vehicle treatment produced a marked fever response in control animals, which was significantly blunted in intracerebroventricularly CRH-treated rats. Although free corticosterone levels reached similar peak concentrations in both intracerebroventricularly vehicle- and CRH-infused groups after LPS, this response was delayed significantly by approximately 1 hr in the intracerebroventricularly CRH-treated animals. Microdialysis experiments showed no changes in basal extracellular levels of serotonin and 5-hydroxyindoleacetic acid in intracerebroventricularly CRH-infused animals. Injection of LPS in intracerebroventricularly CRH-treated rats produced a blunted 5-HT response and a delayed onset of behavioral inhibition and other signs of sickness behavior. Assessment of the endotoxin-induced cytokine responses showed significantly enhanced plasma interleukin-1 (IL-1) and IL-6 bioactivities in the intracerebroventricularly CRH-infused animals 3 hr after injection of LPS, whereas tumor necrosis factor bioactivity responses were not different. Our data demonstrate that chronically elevated brain CRH levels produce marked changes in basal (largely CRH regulated) physiological and behavioral processes accompanied by aberrant responses to an acute challenge. The present study provides evidence that chronic CRH hypersecretion is an important factor in the etiology of stress-related disorders.

Animals↗
PubMed1997

Endocrine profile and neuroendocrine challenge tests in transgenic mice expressing antisense RNA against the glucocorticoid receptor.

A transgene expressing antisense RNA complementary to a fragment of the glucocorticoid receptor cDNA was incorporated into the mouse genome and resulted in a transgenic animal that has decreased glucocorticoid receptor function. The transgenic mice showed basal plasma ACTH and corticosterone levels similar to those of the normal control animals. We have further investigated changes in HPA axis regulation by use of different neuroendocrine challenge tests including a dexamethasone suppression test (DST). In comparison to normal mice, a tenfold higher dose of dexamethasone (i.e. 20 micrograms/100 g body weight) was required to suppress the basal corticosterone levels of transgenic mice. Dexamethasone (2 micrograms/100 g body weight) produced a long-lasting suppression of plasma ACTH and corticosterone levels in control mice, whereas in transgenic animals only a short-lasting decrease in ACTH levels was apparent. Corticotropin-releasing hormone (CRH) administration resulted in an enhanced response in plasma ACTH levels in transgenic mice, whereas the corticosterone response was markedly reduced. The discrepancy between ACTH and corresponding corticosterone secretions in transgenic mice could be attributed, in part, to a reduced sensitivity of the adrenal gland to stimulation by ACTH. Pituitaries of transgenic mice contained about 50% less proopiomelanocortin (POMC) mRNA than those of control animals. No significant differences were noted in the ACTH or protein contents of normal and transgenic mice pituitary glands although a slight increase in protein content of the transgenic mouse adrenal gland was apparent. In conclusion, transgenic mice with impaired GR function show major disturbances in HPA axis regulation which seem to be caused by the primary defect in conjunction with secondary modifications in, amongst others, pituitary CRH receptor system(s), sympathetic output and adrenal development. This mouse is therefore a useful model to study the consequences of life-long defective GR function and HPA axis regulation in general.

Adrenal Glands↗
PubMed1997

Increased stress-induced adrenocorticotropin response after long-term intracerebroventricular treatment of rats with antisense mineralocorticoid receptor oligodeoxynucleotides.

Brain corticosteroid receptors, the type 1 mineralocorticoid receptor (MR) and the type 2 glucocorticoid receptor (GR), are involved in the regulation of neuroendocrine and behavioral responses during ongoing and stressful conditions. To further investigate the role of MR in these responses, we treated male Wistar rats intracerebroventricularly (icv) for 1 week with an 18-base end-capped phosphorothioate-protected antisense oligodeoxynucleotide (ODN) directed against MR mRNA (MR-AS). A mixed bases sequence (MR-MB) and vehicle (0.9% saline) served as controls. The ODN solution was administered by continuous infusion (1 microgram/0.5 microliter/h) via an icv cannula connected with polyethylene tubing to a subcutaneously implanted Alzet miniosmotic pump. No nonspecific effects of the ODNs, such as signs of sickness behavior or loss of body weight, were observed at any time during the treatment. The MR-AS treatment produced a 21% decline in hippocampal MR concentrations. Hippocampal GR levels were not affected by the treatment. MR and GR levels after MR-MB treatment were similar to those found after treatment with the vehicle. In situ hybridization experiments using an [35S]-labeled antisense MR probe showed that hippocampal MR mRNA levels were increased in MR-AS-treated rats. No changes were found in basal early morning levels of plasma ACTH and corticosterone which is consistent with the lack of any changes in adrenal and thymus weight. When rats were socially defeated for 10 min by a male and female resident and then placed for 5 min in the elevated plus-maze, no changes in the anxiety-like behavior were observed in MR-AS-treated animals. However, MR-AS-treated rats killed immediately after the behavioral test had markedly higher plasma ACTH, but not corticosterone, levels than the MR-MB and saline controls. In conclusion, down-regulation of the brain MR produces an enhanced responsiveness of ACTH to stressful situations which appears to be accompanied by a reduced sensitivity of the adrenal gland to ACTH.

Adrenocorticotropic Hormone↗
PubMed1997

Hypothalamic-pituitary-adrenocortical axis changes in a transgenic mouse with impaired glucocorticoid receptor function.

Recently, a transgenic mouse with impaired glucocorticoid receptor (GR) function was created to serve as an animal model for the study of neuroendocrine changes occurring in stress-related disorders, such as major depression. Here, we investigated the hypothalamic-pituitary-adrenocortical (HPA) axis changes in these transgenic mice. There were no significant differences between basal early morning plasma ACTH and corticosterone levels in normal and transgenic mice. When animals were exposed to a mild stressor, an enhanced response in plasma ACTH was observed in the transgenic mice, whereas plasma corticosterone responses were not different. In view of these differences in plasma ACTH and corticosterone responses, we directed our studies toward the regulation of ACTH secretion on the hypothalamic-hypophyseal level in vitro. Therefore, an in vitro model, the pituitary-hypothalamic complex (PHc) was developed and its ACTH release profile was compared with that of the pituitary (PI) alone. The basal ACTH release by PHc and PI from normal and transgenic mice was similar. Regardless of the strain under study, the basal ACTH release by PI was significantly lower than the release by PHc. Stimulation of tissues with either high K+ (56 mM) or CRH (10 or 20 nM) produced an enhanced ACTH release from both PHc and PI, whereas the response in PI was larger than that in PHC. Moreover, the responses to these stimuli were markedly enhanced in tissues from transgenic mice. In tissues of normal mice, corticosterone inhibited both basal and CRH-stimulated ACTH release more potently in PHc than in PI. Furthermore, the feedback capacity of corticosterone to restrain both basal and CRH-stimulated ACTH release was highly impaired in tissues of transgenic mice, whereas the feedback in PHc appeared to be more affected than that in the PI of these animals. In conclusion, the in vitro data on PHc and PI revealed intrahypothalamic mechanisms operating 1) to fine-tune stimulus-evoked ACTH responses; and 2) to facilitate the negative feedback action of glucocorticoids. Moreover, in the transgenic tissues, the impaired GR function was found to cause augmented stimulus-evoked ACTH responses and an impaired glucocorticoid feedback efficacy which appeared to be mainly defective at the hypothalamic level. Thus, in the transgenic mice with life-long central GR dysfunction we found impaired negative feedback combined with "normal" (i.e. noncompensated) in vivo plasma corticosterone responses. This is a condition with potentially grave pathophysiological consequences and, therefore, this transgenic animal may be regarded as a valuable model for the study of functional glucocorticoid insufficiency at the central nervous system level.

Adrenocorticotropic Hormone↗
PubMed1996

Intracerebroventricular administration of missense oligodeoxynucleotide induces interleukin-6 mRNA expression in brain and spleen of rats.

After intracerebroventricular (i.c.v.) injection of a missense oligodeoxynucleotide (MS-ODN) solution in rats, transcripts of the proinflammatory cytokine interleukin (IL)-6 were induced in hypothalamus, hippocampus, cortex and spleen and increased levels of circulating IL-6 and corticosterone were detected. Moreover, using a biotelemetric method body temperature of rats injected with ODN or Ringer solution was monitored over a period of 24 h after the injection. The i.c.v. injection of ODN induced a fever response which peaked at 6 h post-injection. These observations demonstrate that central administration of ODNs generates an inflammatory response in the central nervous system (CNS) and in the periphery as well.

Animals↗
PubMed1996

Molecular and functional evidence for in vitro cytokine enhancement of human and murine target cell sensitivity to glucocorticoids. TNF-alpha priming increases glucocorticoid inhibition of TNF-alpha-induced cytotoxicity/apoptosis.

Cytokine-induced glucocorticoid secretion and glucocorticoid inhibition of cytokine synthesis and pleiotropic actions act as important safeguards in preventing cytokine overreaction. We found that TNF-alpha increased glucocorticoid-induced transcriptional activity of the glucocorticoid receptor (GR) via the glucocorticoid response elements (GRE) in L-929 mouse fibroblasts transfected with a glucocorticoid-inducible reporter plasmid. In addition, TNF-alpha also enhanced GR number. The TNF-alpha effect on transcriptional activity was absent in other cell lines that express TNF-alpha receptors but not GRs, and became manifest when a GR expression vector was cotransfected, indicating that TNF-alpha, independent of any effect it may have on GR number, has a stimulatory effect on the glucocorticoid-induced transcriptional activity of the GR. Moreover, TNF-alpha increased GR binding to GRE. As a functional biological correlate of this mechanism, priming of L-929 cells with a low (noncytotoxic) dose of TNF-alpha significantly increased the sensitivity to glucocorticoid inhibition of TNF-alpha-induced cytotoxicity/apoptosis. TNF-alpha and IL-1 beta had the same stimulatory action on glucocorticoid-induced transcriptional activity of the GR via the GRE, in different types of cytokine/glucocorticoid target cells (glioma, pituitary, epithelioid). The phenomenon may therefore reflect a general molecular mechanism whereby cytokines modulate the transcriptional activity of the GR, thus potentiating the counterregulation by glucocorticoids at the level of their target cells.

Animals↗
PubMed1996

Steroid receptor-mediated effects of neuroactive steroids: characterization of structure-activity relationship.

Neuroactive steroids rapidly alter neuronal excitability through their action via the cell surface. The 3 alpha-hydroxy ring A-reduced pregnane steroids enhance gamma-aminobutyric acid (GABA)-mediated Cl- currents while pregnenolone sulfate and dehydroepiandrosterone sulfate may exert functional antagonistic properties. Based on our previous findings that the 3 alpha-hydroxy ring A-reduced pregnane steroids allotetrahydroprogesterone and allotetrahydrodeoxycorticosterone may regulate gene expression via the progesterone receptor after intracellular oxidation, we have characterized the effects of a series of natural and synthetic neuroactive steroids at the genomic level using a cotransfection system with various steroid receptor expression vectors and a reporter gene in a human neuroblastoma cell line. Pregnanolone and pregnenolone were able to activate both the chicken and the human progesterone receptor while the synthetic 3 alpha-hydroxylated derivative alphaxalone and dehydroepiandrosterone were active via the chicken progesterone receptor but devoid of transcriptional activity via the human progesterone receptor. Moreover, the antiglucocorticoid activity of dehydroepiandrosterone reported at the systemic level could not be reconstituted in the cellular cotransfection system. None of the neuroactive steroids bound directly to steroid receptors. Thus, their genomic activity appears to be mediated via intracellular metabolization. This study provides evidence for differential genomic effects of neuroactive steroids in a structure-specific and species-specific way that may have impact on the development of these steroids for therapeutic application.

Animals↗
PubMed1996

Activation of serotonergic and noradrenergic neurotransmission in the rat hippocampus after peripheral administration of bacterial endotoxin: involvement of the cyclo-oxygenase pathway.

An endotoxic challenge produces pronounced effects on the immune, endocrine and central nervous systems. However, information on the brain structures and neurotransmitter systems participating in the physiological responses after stimulation of the immune system is still scarce. Using an in vivo microdialysis method is conscious, freely moving rats, the present study describes the effects of an endotoxic challenge on hippocampal serotonergic and noradrenergic neurotransmission. Rats were equipped with a microdialysis probe in the hippocampus, which enables the stress-free measurement of extracellular concentrations of serotonin, noradrenaline and their respective metabolites 5-hydroxyindoleacetic acid and 3-methoxy-4-hydroxyphenylglycol. The behavioral activity was scored by measurement of the time during which rats were active (locomotion, grooming, eating, drinking). In the control rats a significant, positive relationship between the behavioral activity and hippocampal extracellular levels of serotonin, noradrenaline and 3-methoxy-4-hydroxyphenylglycol was found. Intraperitoneally injected bacterial endotoxin (lipopolysaccharide; 100 micrograms/kg body weight) increased extracellular concentrations of serotonin, 5-hydroxyindoleacetic acid, noradrenaline and 3-methoxy-4-hydroxyphenylglycol, whereas the behavioral activity was largely reduced, thus disrupting the correlation between behavioral activity and hippocampal levels of serotonin, noradrenaline and 3-methoxy-4-hydroxyphenylglycol. Intraperitoneal pretreatment of rats with the cyclo-oxygenase inhibitor indomethacin attenuated, but did not completely abolish, the endotoxin-induced increases in hippocampal extracellular levels of serotonin, noradrenaline and their metabolites. From these results it may be concluded that the hippocampal serotonin and noradrenaline neurotransmitter systems are part of the brain circuitry responsive to an endotoxic challenge. Moreover, arachidonic acid metabolites seem to represent important, but not the sole, mediators of the endotoxin-induced changes in hippocampal neurotransmission.

Animals↗
PubMed1996

Combined dexamethasone/CRH test in rats: hypothalamo-pituitary-adrenocortical system alterations in aging.

Alterations of the hypothalamo-pituitary-adrenocortical (HPA) system are well-known phenomena in human aging as well as under stressful conditions and in psychiatric disorders. Among the various neuroendocrine function tests developed so far, the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test, in which DEX-pretreated subjects receive a single dose of CRH, has proved to be the most sensitive measure of subtle changes in HPA system regulation. To further explore the mechanisms underlying these neuroendocrine abnormalities in an animal model, a combined DEX/CRH test was established in young male Wistar rats. Five days before the experiment, the jugular vein was catheterized under halothane anesthesia for subsequent drug infusion and blood sampling. DEX (30 micrograms/kg) administered at 12.00 h, during the diurnal trough, suppressed the diurnal increase in circulating corticotropin (ACTH) and corticosterone between 18.00 and 20.00 h, during the acrophase. Subsequent CRH (50 ng/kg) infused at 20.00 h provoked a minimal escape from DEX suppression, indicated by a slight increase in ACTH and corticosterone secretion. Therefore, the combination of 30 micrograms/kg DEX given at 12.00 h followed by pituitary-adrenal system stimulation with 50 ng/kg CRH at 20.00 h was defined as the standard DEX/CRH test procedure and was then used in young (3-6 months) and aged male Wistar rats (20-24 months). After DEX treatment, basal ACTH levels between 18.00 and 20.00 h were significantly higher in aged than in young rats (77.6 +/- 23.2 vs. 19.9 +/- 0.9 pg/ml; p < 0.01), indicating resistance of the HPA system to the suppressive effect of DEX. In addition, the ACTH response to subsequent CRH was significantly higher in aged than in young animals (area under the concentration time curve: 3,670 +/- 2,230 vs. 294 +/- 112; p < 0.05). Thus, the HPA system appeared to be profoundly dysregulated in aged male Wistar rats. The elevated basal ACTH levels reflect glucocorticoid nonsuppression, suggesting negative feedback impairment. This is further supported by the elevated ACTH response to a subsequent CRH challenge, which, in addition, may indicate changes in the endogenous synergistic mechanisms of CRH with other corticotropic factors, for instance vasopressin. In summary, the DEX/ CRH test revealed HPA system alterations in aging and can be applied in future studies to further explore the mechanisms underlying the neuroendocrine disturbances during (psycho) pathological states.

Adrenal Cortex↗
PubMed1995

Intraperitoneal administration of bacterial endotoxin enhances noradrenergic neurotransmission in the rat preoptic area: relationship with body temperature and hypothalamic--pituitary--adrenocortical axis activity.

A combined in vivo microdialysis/biotelemetry method in freely moving rats was used to study the effects of an endotoxic challenge on brain neurotransmission, hypothalamic-pituitary-adrenocortical (HPA) axis activity, autonomic functions and behaviour. Rats were equipped with a microdialysis probe in the preoptic area and a transmitter for biotelemetry in the peritoneal cavity. Time-dependent changes in noradrenergic and serotonergic neurotransmission, and HPA axis activity were monitored by measuring noradrenaline, serotonin, their metabolites and free corticosterone concentrations in dialysates. Core body temperature, heart rate and locomotion were measured simultaneously by biotelemetry. In addition, total behavioural activity was scored by measuring the time during which rats were active. Intraperitoneal administration of endotoxin (lipopolysaccharide; 100 micrograms/kg body weight) caused a pronounced increase in preoptic extracellular concentrations of noradrenaline and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG; 500 and 400% of baseline respectively). No effect was found on preoptic concentrations of serotonin, although the levels of its metabolite 5-hydroxyindoleacetic acid were slightly elevated (120% of baseline). Intraperitoneal lipopolysaccharide caused a marked increase in corticosterone levels, a decline in behavioural activity, and biphasic rises in body temperature and heart rate. Analysis of the time curves revealed that noradrenaline rose in parallel with the first increase in body temperature and the increase in corticosterone levels. Moreover, maximum noradrenaline levels were reached approximately 60 min earlier than the peak in body temperature and corticosterone concentrations. Intraperitoneal pretreatment with the cyclo-oxygenase inhibitor indomethacin prevented the lipopolysaccharide-induced changes in body temperature, heart rate and behavioural activity, whereas the changes in noradrenaline, MHPG and corticosterone were largely, but not completely, reduced. Taken together, the results show that an endotoxic challenge results in a highly differentiated response in brain neurotransmission. We postulate that the profound increase in preoptic noradrenergic neurotransmission may be related to the lipopolysaccharide-evoked induction of fever and/or activation of the HPA axis.

Adrenal Glands↗
PubMed1995

Glucocorticoids accelerate anti-T cell receptor-induced T cell growth.

To study steroid regulation of cell-mediated immunity, we used anti-TCR-stimulated rat splenic lymphocyte mitogenesis as our experimental paradigm. Surprisingly, we found that the principal glucocorticoid of the rat, corticosterone (CORT), potently enhanced anti-TCR-induced lymphocyte proliferation after 2 to 3 days in culture, followed by inhibited cell growth after 5 to 7 days. Thus, glucocorticoids appeared to accelerate anti-TCR-induced lymphocyte mitogenesis. This effect occurred at physiologic concentrations (50-1000 nM), which are known to be released in vivo after an immune challenge. Kinetic experiments showed that CORT had to be present within 60 min after the initiation of TCR activation to produce maximal enhancing effects; a delay of 2 h or more left CORT ineffective. The lymphocytes incubated with CORT may have an increased sensitivity to IL-2 because 1) CORT suppressed IL-2 production throughout the culture period, and 2) an anti-IL-2R mAb completely blocked both control and CORT-treated anti-TCR-induced lymphocyte proliferation. Although the IL-2R alpha- and beta-chain mRNA concentrations were not altered in CORT-treated splenocyte cultures, we observed by FACS analysis an increased expression of the IL-2R alpha-chain on CORT-treated TCR alpha beta + and CD4+ T cells after 48 to 72 h of culture, suggesting an increased sensitivity of these T cells to IL-2 during the phase of enhanced proliferation. These results demonstrate a clear distinction between the enhancing effects of glucocorticoids on anti-TCR-induced lymphocyte proliferation and their well known inhibitory actions. Thus, the present study expands the regulatory role of glucocorticoids in cellular immunity, adding a novel effective stimulatory component to their inhibitory properties.

Animals↗