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F J Tilders

Publications and source records attributed to F J Tilders.

At least 73 records · Page 4Linked to original sources
PubMed1994

Induction of plasma interleukin-6 by circulating adrenaline in the rat.

Adrenaline, which is secreted from the adrenal medulla during stress, is considered to be involved in the control of inflammation and immune responses. Therefore, we studied the effects of adrenaline on the plasma levels of one of the major pro-inflammatory cytokines, interleukin-6 (IL-6). Here we describe that in rats, SC administration of adrenaline induces a dose-dependent increase in plasma IL-6 concentrations, reaching its maximum after 2 h. In addition, intravenous (IV) infusion of adrenaline in a dose resulting in circulating adrenaline concentrations similar to those observed during stress, enhanced heart rate and increased plasma IL-6 concentrations. The increase in plasma IL-6 in response to adrenaline given by subcutaneous (SC) route and by IV infusion could be blocked by the beta-adrenergic receptor antagonist l-propranolol but not by d-propranolol. Based on these data we conclude that under physiological conditions circulating adrenaline may be involved in the control of IL-6 production, and thereby may modulate inflammatory responses.

Adrenal Medulla↗
PubMed1994

Activation of the hypothalamus-pituitary-adrenal axis by bacterial endotoxins: routes and intermediate signals.

Peripheral administration of endotoxin induces brain-mediated responses, including activation of the hypothalamus-pituitary-adrenal (HPA) axis and changes in thermoregulation. This paper reviews the mechanisms by which endotoxin affects these responses. The effects on thermoregulation are complex and include macrophage-dependent hyperthermic and hypothermic responses. Low doses of endotoxin, given IP, activate peripheral macrophages to produce interleukin (IL)-1 beta, which enters the circulation and acts as a hormonal signal. IL-1 may pass fenestrated endothelium in the median eminence to stimulate corticotropin-releasing hormone (CRH) secretion from the CRH nerve-terminals. In addition, IL-1 may activate brain endothelial cells to produce IL-1, IL-6, prostaglandins, etc., and secrete these substances into the brain. By paracrine actions, these substances may affect neurons (e.g., CRH neurons) or act on microglial cells, which show IL-1-induced IL-1 production and therefore amplify and prolong the intracerebral IL-1 signal. In contrast, high doses of endotoxin given i.v. may directly stimulate endothelial cells to produce IL-1, IL-6, and prostaglandin-E2 (PGE2) and thereby activate the HPA axis in a macrophage-independent manner.

Adrenocorticotropic Hormone↗
PubMed1994

Similar age related increase of vasopressin colocalization in paraventricular corticotropin-releasing hormone neurons in controls and Alzheimer patients.

Recent studies on experimental animals showed that long term activation of the hypothalamo-pituitary-adrenal axis is associated with increased vasopressin (AVP) colocalization in paraventricular corticotropin-releasing hormone (CRH) neurons. In the present study we estimated the fraction of CRH neurons in which AVP is colocalized by double label immunocytochemistry in hypothalami of 10 control subjects of 21-91 years of age and 10 age-matched Alzheimer patients. CRH neurons in the paraventricular nucleus (PVN) of Alzheimer patients and control subjects showed similar age dependent increases in AVP colocalization. Based on this parameter, it seems that CRH neurons of Alzheimer patients are not overactivated as compared to age-matched controls, but e.g. changes in m-RNA for CRH should still be established.

Adult↗
PubMed1994

Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients.

The hypothalamo-pituitary-adrenal (HPA) axis is known to be activated in depressed patients. Although direct evidence is lacking, this activation is hypothesized to be due to hyperactivity of corticotropin-releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus (PVN). Recent immunocytochemical studies in experimental animals and in humans showed that the number of CRH-expressing neurons correlated with the activity of these neurons. In addition, colocalization of AVP in CRH neurons has been shown to be an index for the secretory activity. Therefore, we estimated the total number of CRH-immunoreactive neurons and their fraction showing colocalization with AVP in the PVN of 10 control subjects and of 6 depressed patients who were diagnosed to be suffering from a major depression or a bipolar disorder. The mean total number of CRH-expressing neurons of the 6 depressed patients was four times higher, and the number of CRH neurons co-expressing AVP was almost three times higher than those in the control group. We also determined the two activity parameters of CRH neurons in the PVN of 2 subjects with a depressive organic mood syndrome or a depressive disorder not otherwise specified. In these two 'non-major depressed' subjects, the activity parameters of CRH neurons were comparable to those of control subjects. Our observations strongly support the hypothesis that CRH neurons in the PVN are hyperactivated in major depressed patients. This hyperactivity might be causally related to at least part of the symptomatology of depression.

Adult↗
PubMed1993

Functional impairment of hypothalamic corticotropin-releasing factor neurons with immunotargeted toxins enhances food intake induced by neuropeptide Y.

Previous work has shown that administration of corticotropin-releasing factor (CRF) into the lateral ventricle antagonizes the orexigenic effect of neuropeptide Y (NPY), and central injection of CRF antagonist, alpha-helical CRF(9-41) enhanced NPY-induced food intake in satiated rats. The aim of the present study was to determine the effects of selective inactivation of hypothalamic CRF neurons on food intake induced by NPY injection and to delineate which hypothalamic nucleus is involved in this NPY/CRF interaction related to the regulation of food intake. Impairment of CRF neuron function by immunotargeting of a ricin A chain toxin with a monoclonal antibody to CRF (CRF-MAb) has been previously reported. Administration of CRF-MAb/toxins into the paraventricular nucleus (PVN) two weeks prior to testing produced markedly enhanced eating induced by injection of NPY into the same nucleus. This effect was accompanied by a 60% decrease in CRF content within the hypothalamus and a 43% decrease of CRF in the median eminence, a site of projection of CRF neurons from the PVN. In contrast, injection of CRF-MAb/toxins into the ventromedial nucleus of the hypothalamus (VMH) did not modify the feeding induced by NPY injection into this hypothalamic area. Systemic pretreatment with the synthetic glucocorticoid dexamethasone at a dose known to downregulate the levels of CRF in the PVN also enhanced the feeding induced by intra-PVN injection of NPY. This suggests that an equilibrium between CRF and NPY neuronal function within the PVN may play an important role in the regulation of food intake. This interactive mechanism may provide some partial explanation of the eating disorders related to stress, in particular anorexia nervosa.

Animals↗
PubMed1993

Localization of corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the human hypothalamus; age-dependent colocalization with vasopressin.

Immunocytochemical staining, using a monoclonal antibody against corticotropin-releasing hormone, was performed on hypothalami of 13 human subjects between 23 and 91 years of age who had not suffered from a primary neurological or psychiatric disease. Corticotropin-releasing hormone (CRH) immunoreactivity was present in neurons of the paraventricular nucleus (PVN) and in their fibers running to the median eminence. The CRH-positive neurons were scattered throughout the PVN, but in the rostral part relatively few cells were present. There were large individual differences in the number and staining intensity of CRH neurons in the PVN and in the staining intensity of the median eminence. These differences seemed not to be attributed to age, sex, postmortem delay, fixation time or hour of death. In the rat, too, no relationship was found between a postmortem delay of up to 24 h and CRH staining intensity of the median eminence. Since the distribution of CRH-immunoreactive neurons in the human PVN strongly overlap with vasopressin, colocalization of these peptides was investigated in a double label study and indeed found in subjects ranging between 43 and 91 years of age. However, cells staining for only one of the peptides were also observed. The vasopressin cells had a mean cellular profile area which was 2.3 times as large as the CRH cells and 2.2 times as large as the CRH and vasopressin containing neurons. In younger subjects (23-37 years of age) no colocalization of the two peptides was seen. The age-dependent colocalization of CRH with vasopressin is interpreted as a sign of increased activation of the CRH neurons with age.

Adult↗
PubMed1993

Adrenaline and the relationship between neurosomatism, aerobic fitness and mental task performance.

The influence of neurotic instability as manifested by functional somatic complaints (neurosomatism) and aerobic fitness on responses to mental stress and to intravenous adrenaline infusions were investigated in 44 university students. Adrenaline-induced changes from resting levels in state anxiety and somatic anxiety were significantly more pronounced in high than in low neurosomatic subjects and all anxiety ratings were generally negatively related to aerobic fitness. Cardiovascular reactivity was induced by mental stress and by adrenaline infusions, but was not altered by neurosomatism. In individuals assumed to be characterized by a susceptibility to adrenergic effects, interference of adrenaline-induced arousal with cognitive performance may not occur. In contrast, a further increase in performance may occur when adrenaline is infused. Performance measures correlated negatively with anxiety during the baseline task and the placebo task, but this negative relation was absent during the adrenaline infusion and was replaced by positive relations between performance and aerobic power. The complex relations between bodily symptoms of anxiety, aerobic fitness and mental stress are discussed.

Adaptation, Psychological↗
PubMed1993

Is vasopressin preferentially released from corticotropin-releasing factor and vasopressin containing nerve terminals in the median eminence of adrenalectomized rats?

The effects of adrenalectomy (ADX) on the amounts of immunoreactive corticotropin-releasing factor (CRFi) and arginine vasopressin (AVPi) that are stored in the zona externa of the median eminence (ZEME) were investigated by means of quantitative immunocytochemistry. Although ADX of male Wistar rats for 1 week or 4 weeks did not affect CRFi in the ZEME as compared to sham-operated or intact controls, AVPi showed a progressive accumulation. The ratio of AVPi over CRFi in the ZEME had already increased 1 day after ADX. However, it should be noted that the exact changes in CRFi and AVPi as measured by radioimmunoassay and/or quantitative immunocytochemistry were dependent on the substrain of rats used. The secretion rate of CRFi and AVPi was estimated in 1 week and 4 week ADX rats, by measuring the disappearance rate of CRFi and AVPi from the ZEME after blockade of fast axonal transport, by a low non-toxic dose of colchicine (5 micrograms per rat). In contrast to intact rats, where this dose of colchicine did not affect CRFi or AVPi in the ZEME, ADX rats showed a progressive depletion of the CRFi and AVPi stores as measured 2.5 and 5 h later. In 1 week ADX rats, CRFi and AVPi both disappeared at a rate of 7% to 8% of their stores per hour. In contrast, after 4 weeks of ADX the fractional disappearance rates of CRFi and AVPi were different and were 3% and 8% of the content per hour, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗
PubMed1993

Short inescapable stress produces long-lasting changes in the brain-pituitary-adrenal axis of adult male rats.

Recently, we reported that rats exposed to a single and short session of inescapable footshocks showed alterations in behavioural response to environmental stimuli which developed progressively over a week and remained present for at least 28 days. The aim of the present study was to investigate whether these behavioural changes were accompanied by alterations in the brain-pituitary-adrenal axis. Male Wistar rats were subjected to 10 inescapable footshocks (S) of 6 s duration and 1 mA intensity during a period of 15 min. Control rats (C) were placed in the shock apparatus for 15 min without receiving shocks. The effects of these experimental procedures were studied 14 days later. Exposure to shocks did not affect basal plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT). However, the novelty-induced ACTH response was increased in S rats as compared to C rats whereas the CORT response did not differ between C and S rats. The ACTH content of the anterior pituitary gland and adrenal weight were not affected by exposure to inescapable footshocks 14 days earlier. Quantitative immunocytochemistry of vasopressin (AVP) and corticotropin-releasing factor (CRF) in the external zone of the median eminence showed that prior footshock exposure increased the AVPi stores to 167% as compared to C rats, whereas CRFi content was not changed. In addition, S rats showed increased mineralocorticoid (MR) and glucocorticoid (GR) receptor binding capacity in the hippocampus as compared to C rats, whereas affinities were not affected. We conclude that a single and short session of inescapable footshocks has long-lasting effects on brain-pituitary-adrenal functioning concomitant with behavioural alterations.

Adrenocorticotropic Hormone↗
PubMed1993

Stress-induced increase in vasopressin and corticotropin-releasing factor expression in hypophysiotrophic paraventricular neurons.

The concerted action of CRF and vasopressin (VP) plays a critical role in regulating ACTH release from anterior pituitary cells. In this study, we have explored the expression of these neurohormones in hypophysiotropic paraventricular neurons after repeated exposure of rats to immobilization stress. Cell by cell quantitative in situ hybridization was used to evaluate the steady state level of mRNAs coding for VP and CRF. We found that 16 daily stress exposures resulted in a significant increase in the average cellular level of CRF and VP mRNAs (150% and 200% of control levels, respectively). Moreover, in the repeatedly stressed group, the number of VP-expressing parvicellular neurons was approximately doubled relative to the control value. Using quantitative immunoelectron microscopy, VP- and CRF-immunoreactive sites were assessed in the dense core vesicle compartment of CRF axon terminals in the external zone of the median eminence. We found that after repeated stress, the immunolabeling of VP was augmented, while that of CRF was slightly decreased. Concurrently, we observed a significant increase in the proportion of CRF nerve terminals that were VP positive (from 50% in controls to 90% in stressed animals). We conclude that the observed changes in CRF neurons may represent a physiological response to increased functional demand and may lead to alterations in the composition of the ACTH-releasing signal.

Animals↗
PubMed1993

Human recombinant interleukin-1 receptor antagonist prevents adrenocorticotropin, but not interleukin-6 responses to bacterial endotoxin in rats.

The present study was designed to analyze the role of endogenous interleukin-1 (IL-1) in the ACTH, corticosterone (CORT), and IL-6 responses of rats to bacterial endotoxin. Recombinant rat IL-1 beta (rIL-1 beta) when given ip resulted in dose-dependent increases in plasma ACTH, CORT, and IL-6 concentrations. Plasma ACTH and CORT responses could be induced by low rIL-1 beta doses that did not elevate plasma IL-6 levels. The half-maximally effective dose of rIL-1 beta was less than 0.6 microgram/kg for the ACTH and CORT responses and higher than 2.5 micrograms/kg for the IL-6 response. Time-course studies indicated that plasma ACTH and CORT concentrations were already elevated 30 min after the injection of rIL-1 beta (2.5 micrograms/kg, ip), with peak values after 1-2 h, followed by a subsequent decline. In contrast, plasma IL-6 concentrations became elevated 2 h after the injection of rIL-1 beta. In another set of experiments, the administration of endotoxin resulted in a dose-dependent elevation of the plasma ACTH, CORT, and IL-6 concentrations. The dose-response characteristics for ACTH, CORT, and IL-6 were different. The half-maximally effective dose for the ACTH and CORT, and IL-6 responses were approximately 2.5 micrograms/kg and more than 10 micrograms/kg, respectively. Time courses of plasma ACTH, CORT, and IL-6 responses to endotoxin (2.5 micrograms/kg, ip) were similar, with peak values measured after 2 h. When given alone, the human IL-1 receptor antagonist (IL-1RA; 1 or 2.5 mg/kg, ip) did not affect resting plasma ACTH and CORT concentrations and reduced plasma IL-6 concentrations in one experiment. At a dose of 1 mg/kg, IL-1RA inhibited ACTH and IL-6 responses to rIL-1 beta (2.5 micrograms/kg, ip) by 75% and 90%, respectively. Administration of IL-1RA (2.5 mg/kg, ip) 30 min after endotoxin (2.5 micrograms/kg, ip) completely prevented the ACTH response and partially inhibited the CORT response, but did not affect the IL-6 response measured 2.5 h after endotoxin administration. We conclude that 1) IL-1 receptors are involved in the ACTH and IL-6 responses to rat IL-1 beta; 2) the ACTH response, but not the IL-6 response, to a low dose dose of endotoxin in rats requires IL-1 receptor activation by endogenous produced IL-1; and 3) circulating IL-6 is not a prime mediator involved in ACTH and CORT responses to low doses of rIL-1 beta and endotoxin.

Adrenocorticotropic Hormone↗
PubMed1992

Repeated stress enhances vasopressin synthesis in corticotropin releasing factor neurons in the paraventricular nucleus.

The effect of repeated stress on corticotropin-releasing factor (CRF) and vasopressin (AVP) synthesis in parvocellular neurons of the paraventricular nucleus (PVN) was studied by means of double label immunocytochemistry. Once daily immobilization of male rats for 16 days leads to a 75% increase in the number of CRF immunoreactive neurons, but a 5-fold elevation in the number of AVP containing CRF cell bodies. These results demonstrate that repeated stress activates AVP synthesis in CRF neurons.

Animals↗
PubMed1992

Effects of anxiolytic and antidepressant drugs on long-lasting behavioural deficits resulting from one short stress experience in male rats.

Exposure of male Wistar rats to one single session of ten inescapable footshocks induces changes in the behavioural responses to environmental stimuli as measured in the "noise test" 14 days later. Shocked (S) rats showed decreased locomotion and rearing during the first 3 min of exposure to a novel environment compared to control (C) rats. When the 85 dB background noise was switched off a marked immobility response emerged in S rats, concomitant with a further decrease in locomotion and rearing. In response to noise off, C rats showed hardly any immobility and a much smaller reduction in locomotion and rearing compared to S rats. These long-lasting changes in behaviour were not reversed by acute treatment with the antidepressants fluvoxamine (3.0-30.0 mg/kg) and desmethylimipramine (DMI, 2.5-10.0 mg/kg) injected IP 30 min before the noise test on day 14 following the shock session. Chronic treatment (day 1 to day 14) with fluvoxamine or DMI did not reverse the behavioural deficits induced by shock exposure. Diazepam (0.6-5.0 mg/kg) administered acutely only reversed the effects of shock on locomotion during the first 3 min of the noise test. Chronic treatment with diazepam normalized the shock-induced decrease in locomotion and attenuated the rearing decrease during the first 3 min of the test, and partially restored shock-induced changes in behavioural response to switching off the noise. The most potent drug in this study was the 5-HT1A receptor agonist flesinoxan (0.3-3.0 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Hormonal reactions to fighting in rat colonies: prolactin rises during defence, not during offence.

Male Wistar rats living in colonies of 4 males plus 4 females were compared to noncolony males, cohabitating with a female. Irreversible dominance relationships developed between one dominant male (D) and three subordinates (S). Dominants developed high basal testosterone levels and large preputial glands. Subordinates had reduced preputial glands despite normal testicle weights and normal basal testosterone levels. Basal corticosterone was elevated in both ranks, in S more so than in D, while in acute encounters both ranks showed a similar increase in the corticosterone-to-ACTH ratio. They also underwent a similar reduction in thymus weight, while an increase in adrenal weight was more pronounced in D. In D-S-I encounters, during which D simultaneously attacked S and an intruder (I) for 20 minutes, both defenders showed a 3-4 fold increase in plasma prolactin, while in the offensive dominant the level remained low. Similar, but weaker hormonal contrasts between offence and defence were found for beta-endorphin, ACTH, and corticosterone, while alpha-MSH and testosterone did not discriminate. In our view, the marked hyporesponsiveness of prolactin to acute offence may be associated with a specific offensive setting of dopaminergic inhibitory and beta-adrenergic stimulatory influences.

Adrenocorticotropic Hormone↗
PubMed1992

Inescapable footshocks induce progressive and long-lasting behavioural changes in male rats.

Long-term behavioural consequences of exposure to a brief (15 min) session of inescapable footshocks (10 x 6 s, 1 mA) were investigated in male rats. The time course of the effects of inescapable footshocks was assessed by studying the behaviour of groups of rats at different post-stress intervals. Footshocked rats (S) did not differ from control (C) rats (exposed to the shock box for 15 min) in their behavioural response to an open field whether tested 1 h or 4 h post-stress. However, one day after shocks, S rats showed less locomotion and rearing, and more immobility and attention as compared to C rats. At 7 days or 14 days post-stress, S rats exhibited decreased locomotion, rearing, sniffing, and grooming, and increased immobility, attention, and defecation relative to C rats. In a second experiment, we investigated whether footshocks affect the behavioural response to a sudden drop in background noise during exposure to a novel environment. At 21 days post-stress, S rats showed a markedly enhanced immobility response to this stimulus as compared to C rats. In order to investigate whether rats could be exposed repeatedly to the open field without affecting the differences in behaviour between the two treatment groups, C and S rats were tested in an open field for the first time at 7 days post-stress, which yielded the typical effects of footshocks. When these rats were exposed to a second open-field test one week later, the behavioural responses of C and S rats were not different.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Characterization of stress-induced long-term behavioural changes in rats: evidence in favor of anxiety.

Recently, we reported that rats exposed to one brief session of inescapable footshocks showed a gradually developing and long-lasting decrease in behavioural activity and an increase in defecation in an open field. The aim of the present study was to further characterize the long-lasting changes in behavioural responsiveness to environmental stimuli. For this purpose, behavioural paradigms validated as tools in the preclinical study of the psychobiology of depression were used. Footshocked rats (S) showed a decreased response latency in an one-way avoidance-escape task and decreased immobility in a forced swim test as compared to nonshocked control rats (C) 14 days after shock exposure. These S rats showed decreased behavioural activity and increased defecation as compared to the C rats in an open field test carried out 28 days after footshock exposure. In addition, footshock exposure did not affect the preference for or consumption of a 0.05% saccharin solution on a long-term basis, although a decreased consumption of this solution was evident in S rats on day 1 postshock. These S rats showed an exaggerated immobility response to a sudden reduction in background noise level compared to C rats while placed in a novel environment on day 11 postshock. We conclude that the long-term effects of one short session of inescapable footshocks are not compatible with what is supposed to represent behavioural manifestations of depression in animals. It is argued that the common denominator of shock-induced long-lasting changes is increased behavioural defensiveness, which is more likely related to increased fear and/or anxiety.

Animals↗