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Biomedical subjects

A C Linthorst

Publications and source records attributed to A C Linthorst.

At least 19 recordsLinked to original sources
PubMed2001

Psychological stress increases hippocampal mineralocorticoid receptor levels: involvement of corticotropin-releasing hormone.

We investigated whether acute stressors regulate functional properties of the hippocampal mineralocorticoid receptor (MR), which acts inhibitory on hypothalamic-pituitary-adrenocortical activity. Exposure of rats to forced swimming or novelty evoked a significant rise in density of MR immunoreactivity in all hippocampal subfields after 24 hr, whereas exposure to a cold environment was ineffective. Time course analysis revealed that the effect of forced swimming on MR peaked at 24 hr and returned to control levels between 24 and 48 hr. In pyramidal neurons of CA2 and CA3, marked rises were already observed after 8 hr. Radioligand binding assays showed that corticotropin-releasing hormone (CRH) injected intracerebroventricularly into adrenalectomized rats also produced a rise in hippocampal MR levels; an effect for which the presence of corticosterone, but not dexamethasone, at the time of injection was a prerequisite. Moreover, pretreatment with the CRH receptor antagonist (d-Phe(12),Nle(21,38),alpha-Me-Leu(37))-CRH(12-41) blocked the effect of forced swimming on hippocampal MR levels. To investigate whether the rise in MR levels had any functional consequences for HPA regulation, 24 hr after forced swimming, a challenge test with the MR antagonist RU 28318 was conducted. The forced swimming exposed rats showed an enhanced MR-mediated inhibition of HPA activity. This study identifies CRH as an important regulator of MR, a pathway with marked consequence for HPA axis regulation. We conclude that the interaction between CRH and MR presents a novel mechanism involved in the adaptation of the brain to psychologically stressful events.

Adrenalectomy↗
PubMed2001

Bidirectional effects of corticosterone on splenic T-cell activation: critical role of cell density and culture time.

Glucocorticoids inhibit stimulus-induced T-cell proliferation, an early and essential parameter of cellular immunity. It was recently found however that physiological concentrations of glucocorticoids can also accelerate, not only inhibit, rat T-cell mitogenesis. We investigated mechanism(s) underlying mitogenic actions of glucocorticoids on anti-T-cell receptor (TCR)- and concanavalin A (Con A)-induced T-cell proliferation. Surprisingly, the ability of the glucocorticoid corticosterone (CORT) to either enhance or inhibit T-cell proliferation was found to depend primarily on the cell density and the timing of the cultures. At cell densities up to 1 x 10(5) cells/well (i.e. 'low' density), CORT inhibited T-cell proliferation irrespective of the culture time. In contrast, at cell densities of 2 x 10(5) cells/well and higher ('high' density), CORT potently stimulated T-cell mitogenesis during the first 2-3 culture days, but subsequently inhibited the proliferative response after 5-7 days. The glucocorticoid receptor antagonist RU486 completely abolished the effects of CORT. However, production of the main T cell growth factor interleukin (IL)-2 was inhibited by CORT at both 'low' and 'high' cell densities. In addition, irrespective of cell density, T-cell mitogenesis under either control conditions or in presence of CORT was completely blocked by an anti-IL-2-receptor-alpha-chain (IL-2Ralpha) antibody, indicating that T-cell proliferation was dependent on the IL-2 pathway. Immunofluorescence staining of IL-2Ralpha on CD4+ cells after 2-3 days in culture was increased by CORT, but only on cells cultured at 'high' density. Thus, glucocorticoids increase T-cell responsiveness to IL-2 under conditions of 'high' cell density only. We conclude that glucocorticoids may contribute to a more efficient early stage of cellular immune responses under conditions of intimate cell-to-cell contact (i.e. 'high' cell density), a situation likely to be present in vivo, for instance in lymph nodes. Thus, these findings are relevant to our understanding of the glucocorticoid control of immune function.

Animals↗
PubMed2000

The brain mineralocorticoid receptor: greedy for ligand, mysterious in function.

Glucocorticoids exert their regulatory effects on the hypothalamic-pituitary-adrenocortical axis via two types of corticosteroid receptors: the glucocorticoid receptor and the mineralocorticoid receptor. Whereas the glucocorticoid receptor has a broad distribution in the brain, highest levels of mineralocorticoid receptor are found in the hippocampus. Based on the differential occupancy profile by endogenous glucocorticoids, glucocorticoid receptors are thought to mediate negative feedback signals of elevated glucocorticoid levels, whereas mineralocorticoid receptors control the inhibitory tone of the hippocampus on hypothalamic-pituitary-adrenocortical axis activity. Dysfunction of mineralocorticoid receptors and glucocorticoid receptors are thought to be implicated in stress-related psychiatric diseases such as major depression. Because of its intriguing features, we focus in this review on the mineralocorticoid receptor and provide data which reveal novel aspects of the pharmacology and physiology of mineralocorticoid receptors. Newly obtained results are presented, which help to solve the paradox of why dexamethasone binds with high affinity to mineralocorticoid receptors in vitro, yet binds poorly in vivo. Until recently, mineralocorticoid receptor protein and mRNA levels could only be routinely studied with in vitro cytosol binding assays, in vitro and in vivo receptor autoradiography, Northern blot analysis, and in situ hybridization. These methods are unfortunately hampered by several flaws, such as the necessity of adrenalectomy, no or poor neuroanatomical resolution, the fact that mRNA does not provide the same information as protein, or combinations of these factors. We present immunohistochemical data on mineralocorticoid receptors in the brain obtained by using commercially available antibodies, which alleviate many of these shortcomings. Furthermore, an in vivo microdialysis method is presented which allows the assessment of free corticosterone levels in the brain, which is critical for the study of the pharmacological basis of mineralocorticoid receptor (and glucocorticoid receptor) function. Finally, a novel aspect of the regulation of mineralocorticoid receptors is described which provides evidence that this receptor system is dynamically regulated. In conjunction with previously reported effects of antidepressants, these results have initiated a new concept on the cause of the hypothalamic-pituitary-adrenocortical axis disturbances often seen in stress-related psychiatric disorders such as major depression.

Animals↗
PubMed2000

New mode of hypothalamic-pituitary-adrenocortical axis regulation: significance for stress-related disorders.

Two types of corticosteroid receptors have been identified in the brain and pituitary that play an important role in the regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis. These glucocorticoid hormone binding receptors are the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Evidently, a tight control of the concentration and function of these receptors is of prime importance for maintaining and regaining homeostasis after stressful challenges. Here, we describe a novel mechanism revealing a rapid upsurge in MR density in the hippocampus (a limbic structure highly involved in HPA axis regulation) after an acute psychologically stressful challenge. This rise in MR is accompanied by a stronger MR-mediated inhibitory control of the HPA axis. Thus, an acute stressful experience results in a reorganization of the HPA axis involving a principal role of the hippocampal MR. This novel mechanism may be of significance for increasing our understanding of the etiology of stress-related disorders.

Animals↗
PubMed2000

Withdrawal symptoms in a long-term model of voluntary alcohol drinking in Wistar rats.

Long-term voluntary alcohol drinking with repeated alcohol deprivation episodes has been suggested as animal model for some aspects of alcoholism. Using a radiotelemetric system, the present study investigated the occurrence of withdrawal symptoms in long-term voluntarily alcohol drinking Wistar rats with (repeated alcohol deprivation group) and without (first alcohol deprivation group) prior alcohol deprivation experience. Six days after transmitter implantation, alcohol bottles were removed, and returned 4 days later. Alcohol deprivation induced hyperlocomotion in both groups. In the repeated alcohol deprivation group, hyperlocomotion was increased at the beginning of the alcohol deprivation phase and decreased during the following dark phase, suggesting that removal of the alcohol bottles might have become a conditioned withdrawal stimulus for this group. Both groups showed an enhanced alcohol intake after representation of alcohol bottles compared to preabstinence intakes (alcohol deprivation effect). However, alcohol intake of the repeated alcohol deprivation group was significantly increased compared to the first alcohol deprivation group at the end of the experiment. It is concluded that repeated alcohol deprivation experience might promote the development of alcohol addiction because of its latent stimulating effect on alcohol drinking that can be unveiled by (presumably mildly stressful) experimental situations.

Alcohol Drinking↗
PubMed2000

Glucocorticoid receptor impairment alters CNS responses to a psychological stressor: an in vivo microdialysis study in transgenic mice.

To study the consequences of impaired functioning of the glucocorticoid receptor (GR) for behavioural, neuroendocrine and neurochemical responses to a psychological stressor, a transgenic mouse expressing antisense RNA against GR was used. Previous studies on these transgenic mice have shown that impairment of GR evolves in disturbed neuroendocrine regulation and certain behavioural responses to stress. Here we investigated putative disturbances on the level of brain neurotransmission in GR-impaired (GR-i) mice using an in vivo microdialysis method. Through a microdialysis probe in the hippocampus, serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and free corticosterone [as an index of hypothalamic-pituitary-adrenocortical (HPA) axis activity] were monitored. Moreover, specific behaviours (e.g. grooming, eating/drinking, sniffing, nest building and locomotion) displayed by the mice during collection of the dialysates were scored. Measurement of dialysate concentrations of corticosterone on days 1 and 3 after insertion of the microdialysis probe showed that the free levels of this glucocorticoid were significantly lower in GR-i mice toward the evening. On day 2 after insertion of the microdialysis probe, baseline values of dialysate corticosterone, 5-HT and 5-HIAA were assessed, after which mice were exposed to a rat placed into their home cage. The rat and mouse were separated by a Plexiglas wall. A positive correlation between baseline hippocampal extracellular levels of 5-HT and 5-HIAA and the time spent performing active behaviours was observed in both genotypes. The main active behaviour performed at the baseline was grooming behaviour. During the rat exposure period, control mice remained mostly sitting and/or lying with their eyes fixed on the rat. Moreover, they showed a profound rise in free corticosterone levels. In contrast, GR-i mice displayed significantly more activities along the separation wall and a trend toward more grooming behaviour, but no increase of free corticosterone. In both mouse lines, exposure to a rat increased hippocampal extracellular levels of 5-HT and 5-HIAA. The rise in 5-HT was, however, more pronounced in the GR-i mice. From these data it may be concluded that life-long GR impairment has profound consequences for behavioural and neuroendocrine responses to a psychological stressor. Moreover, long-term impaired functioning of GR evolves in hyper-responsiveness of the raphe-hippocampal serotonergic system.

Animals↗
PubMed2000

Diurnal variations in lipopolysaccharide-induced sleep, sickness behavior and changes in corticosterone levels in the rat.

Inoculation of rats with microorganisms or microbial constituents that activate host defense promotes non-rapid eye movement sleep (non-REMS) and suppresses REMS. In this study, we evaluated circadian influences on the effects of lipopolysaccharide (LPS) on sleep, sickness behavior and plasma corticosterone levels in the rat. Three sets of experiments were performed. In each, the animals were intraperitoneally injected with vehicle for LPS (30 microg/kg) during 2 consecutive days, at the beginning of either the circadian rest or the activity phase. In experiment 1, sleep-wake behavior and brain temperature were recorded, and in experiment 2, core body temperature, locomotor activity as well as food and water intake. In experiment 3, corticosterone blood levels were measured. The results show that LPS-evoked changes in temperature, sleep and other behavioral parameters depend markedly on the time of day LPS is administered. However, a direct comparison of the LPS data demonstrates that, except for sleep parameters, the absolute time course of the assessed parameters was rather similar between the rest and activity phases. These findings suggest that LPS evokes a state characterized by high temperature and low vigilance, which is reached independently of the circadian phase.

Animals↗
PubMed1999

Impaired glucocorticoid receptor function evolves in aberrant physiological responses to bacterial endotoxin.

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 micrograms/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-1 beta and interleukin-6 was not different between the strains. However, whereas in control mice tumour necrosis factor-alpha 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.

Adrenocorticotropic Hormone↗
PubMed1998

Brain neurotransmission during peripheral inflammation.

It is now well established that an inflammatory challenge as evoked by bacterial endotoxin (LPS) induces autonomic, endocrine, and behavioral responses that are controlled by the brain. However, detailed information on the neuronal pathways and neurotransmitters involved is scarce. We used in vivo microdialysis and biotelemetry in rats to monitor hippocampal and preoptic serotonergic and noradrenergic neurotransmission, body temperature, and heart rate after an i.p. LPS injection. Moreover, free corticosterone levels were measured in the dialysates, and behavioral activity was scored by visual observation. Apart from a biphasic fever response, tachycardia, elevated free corticosterone levels, and sickness behavior, peripheral injection of LPS caused a dramatic increase in preoptic extracellular concentrations of noradrenaline, but no effect on serotonin in this structure. The increase in preoptic noradrenaline levels appears to underlie the first fever phase and may participate in hypothalamic-pituitary-adrenocorticul axis activation. In contrast, whereas LPS had only a moderate effect on hippocampal noradrenaline, a marked increase in hippocampal extracellular serotonin levels was found. Use of the interleukin (IL)-1 receptor antagonist and the cyclooxygenase inhibitor indomethacine learned that IL-1 and prostaglandins are mediators in this response. Our data show that an endotoxin challenge results in highly differentiated changes in brain neurotransmission, probably subserving the coordinate processing of immune information in circuits involved in autonomic, neuroendocrine, and behavioral regulation.

Animals↗
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

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

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

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

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

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↗
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↗