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  • 1
    ISSN: 1432-1459
    Keywords: Key words Multiple sclerosis ; Lymphocytes ; Glucocorticoid ; receptors ; Dexamethasone CRH test
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Although the exact etiology of multiple sclerosis (MS) remains unresolved, immune reactions are believed to be the central pathogenic mechanisms. Endogenous and therapeutic steroid hormones affect the immune system, and inflammatory diseases are associated with activation of the hypothalamic-pituitary-adrenal axis, providing evidence of an immune-endocrine interplay. Function tests in MS have revealed dysregulation of the hypothalamic-pituitary-adrenal system in a substantial proportion of patients. We characterized glucocorticoid receptor (GR) binding in peripheral blood lymphocytes from 39 MS patients and 14 age- and sex-matched controls with respect to dissociation constant and binding capacity, using a whole-cell binding assay with [3H]dexamethasone as the ligand. GR binding parameters did not differ significantly between patients (K d 8.98 ± 1.07 nM, B max 183 ± 29.8 fmol/mg) and controls (K d 9.36 ± 1.17 nM, B max 158 ± 16 fmol/mg). No effect of age, sex, course, duration or severity of disease, or prior steroid treatments was detected. GR binding parameters were analyzed in relation to the results of the combined dexamethasone-CRH test, which reflects corticosteroid receptor function at the hypothalamus, in 30 patients and 9 controls. While controls showed a moderate correlation between binding affinity of the GR in lymphocytes and regulatory function at the hypothalamic level, the patients did not. These data suggest that the physiological relationship between binding and function of the glucocorticoid receptor is disturbed in MS.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Disturbances in serotonergic neurotransmission have been suggested to be closely interlinked with hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system, and are likely to be involved in the pathophysiology of anxiety disorders and major depression. We therefore investigated markers of serotonergic transmission and their modulation by chronic paroxetine in rats selectively bred for high (HAB) or low (LAB) anxiety-related behaviour, both under basal conditions and in response to emotional stress. Hippocampal serotonin 1 A (5-HT1A) receptor mRNA expression was reduced in HAB rats, whereas 5-HT concentrations in hippocampal microdialysates did not differ between HAB and LAB rats under basal conditions. In the hippocampus, overall expression of serotonin transporter binding sites was increased in HAB compared with LAB rats. Exposure to emotional stress failed to increase intrahippocampal 5-HT release in HAB rats whereas LAB rats displayed a physiological, albeit small rise. Chronic paroxetine treatment markedly increased the stress-induced rise in hippocampal 5-HT in HAB, but not LAB rats. This effect may be (at least in part) related to a greater down-regulation of hippocampal serotonin transporter binding sites by paroxetine in HABs compared with LABs, while 5-HT1A receptor expression remained unaffected in this brain area. The findings indicate reduced hippocampal serotonergic transmission in HAB rats as compared with LAB rats, which is evident both at the presynaptic (5-HT release) and the postsynaptic (5-HT1A receptor) level. Chronic paroxetine enhanced the presynaptic responsivity in HAB rats, but not LAB rats, pointing to a preferential efficacy of paroxetine in rats with enhanced anxiety/depression-related behaviour.
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    European journal of neuroscience 7 (1995), S. 0 
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Simultaneous microdialysis in the brain and blood was used to monitor the release of vasopressin and oxytocin within the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei and into the systemic circulation of urethane-anaesthetized male rats before and after central administration of interleukin-1β (IL-1β). Following intracerebroventricular infusion of the cytokine (200 ng/5 μl), the content of vasopressin (up to 278% compared to vehicle-treated control, P 〈 0.01 compared to vehicle-treated control and preinfusion baseline) but not oxytocin (up to 148%, not significant) in 30-min blood microdialysates was found to be increased. This peripheral release was accompanied by a transient rise in vasopressin (up to 163%, P 〈 0.05) and oxytocin (up to 182%, P 〈 0.05) release within the SON, the peak typically occurring during the first and second 30-min collection intervals after IL-1 β respectively. In contrast, in the simultaneously microdialysed PVN, both vasopressin and oxytocin failed to respond to intracerebroventricular IL-1 β. In another series of experiments, IL-1 β was directly infused (20 ng0.5 μl) into either the SON or PVN during microdialysis of the corresponding nucleus. The cytokine caused a significant and immediate rise in intra-SON release of both vasopressin (up to 225%, P 〈 0.01) and oxytocin (up to 178%, P 〈 0.05). Again, in the PVN, nonapeptide release, although tending to be stimulated in response to intranuclear IL-1 β, failed to reach statistical significance. The cytokine-induced central and peripheral release pattern appeared to be independent of the rise in body temperature observed after IL-1 β administration. In a third series of experiments, bilateral administration of IL-1 β into the SON (20 ng/0.5 μl) failed to alter peripheral release of both vasopressin and oxytocin into the systemic circulation. The increase in central nonapeptide release in response to IL-1 β shown in this paper supports the hypothesis that at least vasopressin might act to oppose central effects of the cytokine, including those on thermoregulation and behaviour, in this way contributing to the neuroendocrine-immune dialogue at brain level.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    European journal of neuroscience 5 (1993), S. 0 
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The distribution of interleukin 6 (IL-6) mRNA and IL-6 receptor (IL-6R) mRNA in the brain of adult male rats was studied at the light microscope level by in situ hybridization histochemistry using 35S-labelled oligonucleotides. The transcripts of both genes were localized in the pyramidal neurons and in the granular neurons of the hippocampus, in neurons of the habenular nucleus as well as in the dorsomedial and ventromedial hypothalamus, in the piriform cortex, in scattered neurons of the cortex and in granular cells of the cerebellum. The medial preoptic nucleus and the anterior tip of the lateral ventricle contained mRNA encoding IL-6 and its receptor. Moreover, white matter areas, such as the internal capsule, which consist of only fibres and glial cells, were found to have autoradiographic signals above background. The mRNAs for IL-6 and IL-6R in hippocampus and cerebellum are not different, as shown by Northern blot analyses of RNA isolated from these tissues. We postulate that the cytokine IL-6 is expressed constitutively in discrete regions of the CNS and that it is involved in the mechanisms coordinating metabolic, behavioural and neuroendocrine changes not only during illness but also under normal physiological conditions. Our results suggest that IL-6 mRNA and IL-6R mRNA are colocalized, thus supporting a role of the cytokine in autocrine and paracrine communication.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 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 μg/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 ˜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.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    European journal of neuroscience 15 (2002), S. 0 
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Central administration of corticotropin-releasing hormone increases anxiety-like behaviour and arousal in rodents, and increased anxiety-like behaviour has been shown in mice overproducing corticotropin-releasing hormone on an elevated plus maze and in a dark–light emergence task. However, evidence is accumulating that measures obtained from different anxiety tasks may reflect different aspects of anxiety-like behaviour in animals. We therefore tested mice overproducing corticotropin-releasing hormone in a battery of paradigms, studying spontaneous behaviour after a mild stressor, tasks of innate anxiety-like behaviour (light–dark box), lick suppression (Vogel conflict), conditioned fear, and forced swimming. Exploratory behaviour was studied in a 16-hole board task. Furthermore, pain threshold, water intake, locomotor activity and sensorimotor learning/co-ordination were tested to control for confounding factors. In line with previous findings, increased anxiety-like behaviour of transgenic mice was observed in the light–dark box paradigm. However, no differences were seen in the conflict paradigm. Conditioned fear was decreased 1 h but not 24 h after conditioning in transgenic mice, and immobility was increased in forced swimming in corticotropin-releasing hormone overexpressors. Locomotor activity in a novel open field and on the hole board was reduced in transgenics. Exploratory behaviour (hole pokes) was reduced during initial exploration of an unfamiliar hole board. Moreover, sensorimotor performance on a rotorod was impaired, and water intake was reduced in corticotropin-releasing hormone overproducing mice, while no changes were seen in nociception. No differences in locomotor activity were seen in a second group of mice, tested in a familiar open field. When these animals were challenged with diazepam, transgenic mice were less susceptible to the sedative effects of the drug on locomotor activity. These data suggest that corticotropin-releasing hormone overproduction leads to specific effects in a subset of anxiety paradigms, and that these transgenic mice suffer from a motor deficit in addition to altered anxiety-like behaviour/arousal.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    European journal of neuroscience 12 (2000), S. 0 
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Transgenic mice with impaired glucocorticoid receptor (GR) function were tested for their ability to learn and perform a series of simultaneous visual discriminations which allowed a dissociation between accuracy of discrimination from those of motivation and behavioural disinhibition. Animals were first trained on an operant five-choice simultaneous discrimination autoshaping procedure, followed by a continuous reinforcement schedule on that task. Subsequently, the number of choices was limited to two and data were analysed according to the mathematical methods of signal detection theory (SDT). The effects of GR-antisense expression on accuracy when different rates of responding were required were studied under different fixed ratio response requirements (FR1–FR10). Autoshaping was retarded in transgenic animals and accuracy was impaired in both the five-choice and the two-choice discrimination tasks, although transgenic mice showed clear evidence for learning. Under conditions of low response requirements, transgenic mice showed increased response and cognitive biases, but reduced perceptual bias, and a behavioural disinhibition, characterized by a reduction in errors of omission, decreased response latencies and increased number of responses during the inter-trial interval. Increasing the response requirement improved performance in transgenic animals as reflected by enhanced accuracy. Moreover, transgenics were less susceptible to the deleterious effects of higher response requirements, as indicated by relatively unaffected bias measures in this group, while bias increased in controls. These results indicate that altered performance in GR-antisense transgenic animals cannot simply be interpreted as a mnemonic deficit, but that altered motivation and enhanced impulsive responding may account for some of these impairments.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    European journal of neuroscience 12 (2000), S. 0 
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The ageing process has been shown to have a profound impact on the hypothalamo–neurohypophysial system (HNS) and the hypothalamo–pituitary–adrenocortical (HPA) axis in humans as well as in rodents. Therefore, in this study, the intracerebral and peripheral release patterns of both vasopressin and oxytocin have been studied in aged male Wistar rats under basal conditions and in response to ethologically relevant stressors, using intracerebral microdialysis and chronic blood sampling techniques, respectively. Approximately a twofold higher basal release of arginine vasopressin (AVP) within the hypothalamic paraventricular nucleus (PVN), but not within the supraoptic nucleus (SON), was found in aged rats, whereas basal oxytocin (OXT) release did not differ in comparison with young rats. With increasing age the rise in intra-PVN release of both AVP and OXT was blunted in response to forced swimming. In contrast, the intra-SON release of AVP was unrelated to age. Simultaneously recorded basal secretion of both AVP and OXT from the neurohypophysis into blood was increased in aged rats, with a blunted OXT response to swim stress. Opposed to that, plasma AVP levels remained unchanged in both groups. Basal plasma levels of corticotropin (ACTH) and corticosterone were elevated in aged rats, whereas stress-elicited ACTH and corticosterone responses were indistinguishable. These results indicate age-related changes in the HNS and HPA axis with an enhanced basal activity opposed to a blunted response to stressors with increasing age. The increased basal release of AVP within the PVN suggests a role of intracerebral AVP in age-associated alterations of HPA axis regulation.
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  • 9
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The aim of the present study was to investigate the physiological significance of the neuropeptide arginine vasopressin (AVP) released within the septum, in the behavioural response of rats to stress. In the first experiment, rats were chronically implanted with a microdialysis probe aimed at the mediolateral or ventral septum to monitor the local release of AVP in response to 10 min of forced swimming in 20 °C warm water. Exposure to this stressor caused a significant increase in AVP release in both the mediolateral (174 ± 21%, P 〈 0.01) and ventral septum (220 ± 33%, P 〈 0.01). In contrast, microdialysates collected outside the mediolateral septum or in the lateral ventricle remained at prestress levels throughout the dialysis period. Furthermore, unstressed control animals failed to show significant alterations in vasopressin release in the mediolateral septum. In a second experiment, the introduction of the V1 receptor antagonist d(CH2)5Tyr(Me)AVP into the mediolateral septum via inverse microdialysis concomitant with stressor exposure caused the rats to spend an increased time floating and a reduced time swimming compared to vehicle-treated rats. This effect was acute and also detected 24 h after antagonist administration. Taken together, these findings demonstrate a significant activation of the septal vasopressinergic system in response to swim stress. Furthermore, our data support the view that AVP released within this brain area is involved in the generation of active behavioural strategies aimed at coping with new and challenging situations.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The consequences of glucocorticoid receptor (GR) dysfunction for neuroimmunoendocrine responses to an inflammatory challenge were studied in transgenic mice expressing antisense RNA directed against the GR [GR-impaired (GR-i) mice]. Mice were implanted intraperitoneally with a biotelemetry transmitter to monitor body temperature and locomotion. GR-i mice showed decreased locomotion and body temperature during the dark phase of the diurnal cycle. Intraperitoneal administration of saline caused a rapid increase in body temperature in control mice, which was terminated within 90 min. In GR-i mice, however, body temperature remained elevated for about 6 h. Intraperitoneal injection of endotoxin (10 μg/mouse) produced a biphasic fever in control mice. However, in endotoxin-injected GR-i mice, body temperature was not significantly different from their saline-injected controls during the first 6 h. Body temperature then increased and remained elevated during the night period. Both strains showed hypolocomotion after endotoxin. In a second experiment, mice were injected intraperitoneally with saline or endotoxin and killed after 1, 3, 6 or 24 h. In GR-i mice, endotoxin caused an augmented rise in plasma ACTH, but not in corticosterone levels. The endotoxin-induced increase in serum levels of interleukin-1β and interleukin-6 was not different between the strains. However, whereas in control mice tumour necrosis factor-α levels were below detection at the time points studied, substantial levels of this cytokine were found in the serum of GR-i mice 1 h after endotoxin administration. It may be concluded that life-long impairment of GR evolves in aberrant physiological and humoral responses to an acute inflammatory challenge. These findings expand our understanding about the neuroendocrine and physiological disturbances associated with stress-related disorders.
    Type of Medium: Electronic Resource
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