Biomedical subjects

F Holsboer

Publications and source records attributed to F Holsboer.

At least 145 records · Page 8Linked to original sources

PubMed1998

Neuroactive steroid concentrations following metyrapone administration in depressed patients and healthy volunteers.

BACKGROUND: There is evidence that treatment with the 11 beta-hydroxylase inhibitor metyrapone may represent an alternative treatment strategy in major depression. As a consequence of inhibition of cortisol synthesis the overdrive of corticotropin leads to an accumulation of precursor steroids. However, the effects of metyrapone on the concentrations of endogenous neuroactive steroids that modulate ion channels, e.g., the GABAA receptor, have not yet been studied systematically. METHODS: Therefore, we quantified the concentrations of an array of neuroactive steroids following administration of 1.5 g metyrapone before and after pretreatment with 1 mg dexamethasone in 19 patients suffering from severe depression in comparison to 13 healthy controls by means of a highly sensitive gas chromatography/mass spectrometry analysis. RESULTS: The administration of metyrapone induced a pronounced increase in all neuroactive steroids studied both in patients and controls that was prevented by dexamethasone pretreatment. CONCLUSIONS: Thus, the psychotropic properties of endogenous neuroactive steroids may contribute to the antidepressant properties of metyrapone in the treatment of major depression.

Adrenocorticotropic Hormone↗

PubMed1998

Forced opiate withdrawal under anaesthesia augments and prolongs the occurrence of withdrawal signs in rats.

A newly developed treatment for rapid detoxification of opiate addicts is the use of continuous naloxone/naltrexone administration under general anaesthesia. This method is now introduced in several European countries despite the fact that there is only spare evidence for its effectiveness. Here we report on the assessment of withdrawal symptoms in morphine-dependent rats which received continuous naloxone administration combined with barbiturate anaesthesia. Morphine-dependent rats were implanted with osmotic minipumps filled with either saline or naloxone (delivering 0.5 mg/kg per hour) under barbiturate anaesthesia (lasting for 8 h). Animals were tested daily for the occurrence of withdrawal signs for the subsequent 7 days. All signs of withdrawal which are frequently observed in rats undergoing morphine withdrawal such as body weight loss, diarrhea, writhing, teeth chattering and wet dog shakes were significantly augmented and observed over longer time periods in morphine-dependent animals treated continuously with naloxone versus rats receiving saline. The present study demonstrates that continuous naloxone treatment under anaesthesia worsen and prolongs the detoxification phase in rats. This conflicts with reported clinical observations, and strongly suggests a need for controlled clinical studies before this method enters the everyday clinical routine.

Anesthesia, General↗

PubMed1998

Induction of NF-kappaB activity during haloperidol-induced oxidative toxicity in clonal hippocampal cells: suppression of NF-kappaB and neuroprotection by antioxidants.

Haloperidol (HP), a dopamine receptor antagonist, is cytotoxic to mouse clonal hippocampal HT22 cells in a concentration-dependent manner and causes cell death by oxidative stress. The addition of HP to HT22 cells led to an increase in intracellular peroxides and a time-dependent drop in the intracellular glutathione levels. HP-induced oxidative cell death was prevented by the pineal hormone melatonin, its precursor N-acetyl serotonin, and most effectively by vitamin E (alpha-tocopherol). These antioxidants inhibited the intracellular peroxide accumulation and stabilized the glutathione content of HT22 cells after the challenge with HP. At the molecular level, HP specifically induced the DNA binding activity and the transcriptional activity of the redox-sensitive transcription factor NF-kappaB. This enhanced NF-kappaB activity could be blocked by the neuroprotective antioxidants. The specific suppression of NF-kappaB by its inhibitor IkappaBalpha partially protected the cells against HP, indicating that the activation of NF-kappaB may be involved in HP-induced oxidative cell death in vitro.

Animals↗

PubMed1998

Age- and stimulus-dependent changes in anxiety-related behaviour of transgenic mice with GR dysfunction.

Transgenic mice expressing antisense directed against glucocorticoid receptor (GR) mRNA were used for a longitudinal study on the effects of hypothalamic-pituitary-adrenocortical dysfunction on anxiety-related behaviour and locomotor activity. Compared with age-matched controls and 5-week-old transgenic animals, 13- and 36-week-old transgenic mice made significantly more entries into and spent significantly more time on the open arms of the elevated plus-maze thereby indicating reduced basal anxiety. In contrast, time spent in the central area of the open field was significantly reduced in transgenic animals indicating an enhanced anxiety under conditions of increased stress. Locomotor activity did not differ between transgenic and control animals. Our results indicate that behavioural changes in transgenic mice differ according to the age of the animals and the behavioural paradigm used. Transgenic animals with an impaired GR function may be of help in studying the interaction of ageing, GR function and the development of behavioural abnormalities.

Aging↗

PubMed1998

Reduced activity of hypothalamic corticotropin-releasing hormone neurons in transgenic mice with impaired glucocorticoid receptor function.

Loss of central glucocorticoid receptor (GR) function is thought to be involved in the development of neuroendocrine and psychiatric disorders associated with corticotropin-releasing hormone (CRH) hyperactivity. The possible causal relationship between defective GR function and altered activity of CRH neurons was studied in transgenic mice (TG) expressing antisense RNA against GR. Immunocytochemical studies showed significant reductions in CRH immunoreactive neurons in the paraventricular nucleus (PVN) and in CRH and vasopressin (AVP) stores in the external zone of the median eminence. Concomitantly, stimulus-evoked CRH secretion from mediobasal hypothalami of TG mice in vitro was reduced significantly. However, CRH mRNA levels in the PVN of TG mice were marginally lower than those in wild-type (WT) mice. 125I-CRH binding autoradiography revealed no differences between WT and TG animals in any of the brain regions that were studied. Basal plasma corticosterone (cort) levels and 125I-CRH binding, CRH-R1 mRNA, POMC mRNA, and POMC hnRNA levels in the anterior pituitary gland were similar in WT and TG mice. Intraperitoneal injection of interleukin-1beta (IL-1beta) increased plasma cort levels, CRH mRNA in the PVN, and anterior pituitary POMC hnRNA similarly in WT and TG mice. The injection of saline significantly reduced anterior pituitary CRH-R1 mRNA levels in WT mice, but not in TG mice, whereas IL-1beta produced a decrease in these mRNA levels in both strains. The data show that long-term GR dysfunction can be associated with reduced activity of CRH neurons in the PVN and decreased sensitivity of pituitary CRH-R1 mRNA to stimulus-induced downregulation. Moreover, the hypothalamic changes observed in this model suggest that impaired GR function, at least if present since early embryonic life, does not necessarily result in CRH hyperexpression characteristics of disorders such as major depression.

Animals↗

PubMed1998

C-type natriuretic peptide exerts effects opposing those of atrial natriuretic peptide on anxiety-related behaviour in rats.

As evidence exists that C-type natriuretic peptide (CNP) exerts effects opposing those of atrial natriuretic peptide (ANP), we studied the behavioural properties of CNP after central infusion in rats by their performance in the elevated plus maze. Doses of 0.5 microg and 5 microg i.c.v. had distinct anxiogenic properties. Our data suggest opposing effects of CNP and ANP on anxiety-related behaviour in rats, which appear to be mediated via different receptor occupation and brain regions by a corticotropin-releasing hormone (CRH)-dependent mechanism.

Animals↗

PubMed1998

Cytokine expression and molecular mechanisms of their auto/paracrine regulation of anterior pituitary function and growth.

The pituitary gland expresses cytokines and their receptors. IL-2 receptor transcripts and protein products are co-localized in ACTH-, PRL-, and GH-producing cells (double immunofluorescence). IL-2 and IL-6 (1-1000 IU/ml) are involved in the autocrine/paracrine regulation of normal and tumor (GH3 mammosomatotroph cell line and adenoma cell cultures) anterior pituitary hormone-producing cell growth (cell number, DNA synthesis, c-fos mRNA expression and autoradiography combined with hormone staining). IL-1 regulates the growth of normal pituitary cells but does not act on GH3 cells. IL-1ra, which blocks this action, is expressed in tumoral pituitary (mainly GH- and ACTH-) cells. In ACTH- cells, IL-1 enhances glucocorticoid feedback, stimulating glucocorticoid response element transcriptional activity. Cytokines, through specific functional receptors, act as inter/auto-cellular factors that regulate not only the function but also the growth of anterior pituitary cells.

Animals↗

PubMed1998

High constitutive NF-kappaB activity mediates resistance to oxidative stress in neuronal cells.

Selected clones of the sympathetic precursor-like cell line PC12 (rCl8) are resistant to oxidative cell death induced by the Alzheimer's disease-associated amyloid beta protein (Abeta) and hydrogen peroxide (H2O2). Here, we show that the transcriptional activity and DNA binding activity of the redox-sensitive transcription factor NF-kappaB and its nuclear expression are constitutively increased in rCl8 cells compared with their nonresistant parental PC12 cell (PC12p) counterpart. Suppression of the transcriptional activity of NF-kappaB in rCl8 cells with the synthetic glucocorticoid dexamethasone or by direct overexpression of a super-repressor mutant form of IkappaBalpha, a specific inhibitor of NF-kappaB, reversed the oxidative stress resistance phenotype of these cells and ultimately led to increased cell death after the challenge with H2O2. Dexamethasone treatment also caused an increase in the protein level of IkappaBalpha. Our data show that an increased baseline of NF-kappaB activity may mediate the resistance of these cells of neuronal origin to oxidative stress. Therefore, the presented model may help to identify possible neuronal target genes of NF-kappaB and to further elucidate the molecular basis of the differential sensitivity of neurons in neurodegenerative conditions associated with an increased oxidative burden, such as in Alzheimer's disease.

Animals↗

PubMed1998

Atrial natriuretic hormone decreases endocrine response to a combined dexamethasone-corticotropin-releasing hormone test.

BACKGROUND: An escape from the dexamethasone-induced suppression of pituitary-adrenocortical activity can be provoked by corticotropin-releasing hormone (CRH) in depressed patients, but not in healthy controls. One important antagonist of the CRH-stimulated secretion of corticotropin (ACTH) and cortisol is atrial natriuretic hormone (ANH). METHODS: To study a potential role of ANH in the dexamethasone-CRH test, we investigated 7 healthy men who did not suppress cortisol below 40 ng/mL after they had received 0.5 mg dexamethasone the evening before. RESULTS: We found 1) that the CRH-stimulated ACTH and cortisol secretion was significantly reduced by the administration of ANH in comparison to saline; and 2) that there was an increased pituitary-adrenocortical ratio. CONCLUSIONS: Our results support the view that ANH may also be involved in the frequently observed nonsuppression after dexamethasone during depression. Biol Psychiatry.

Adrenocorticotropic Hormone↗

PubMed1998

The Th1 and Th2 cytokines IFN-gamma and IL-4 antagonize the inhibition of monocyte IL-1 receptor antagonist by glucocorticoids: involvement of IL-1.

Monocytes express IL-1 and IL-1 receptor antagonist (IL-1Ra) in response to lipopolysaccharide (LPS). IL-1 self-induction contributes to the increase in IL-1 following LPS stimulation. LPS-stimulated IL-1 and IL-1Ra production are inhibited by glucocorticoids. In the present work we examined the regulation of IL-1Ra by Th1 cytokine IFN-gamma, Th2 cytokine IL-4, glucocorticoids and IL-1 in human monocytes. We demonstrate that IL-1 contributes to LPS-induced IL-1 Ra expression as shown by IL-1 blockade in LPS-stimulated monocytes using a specific anti-IL-1beta antibody or recombinant IL-1Ra. Glucocorticoids inhibited IL-1beta-stimulated IL-1Ra mRNA expression and protein production. Glucocorticoids inhibited both IL-1-mediated and non-mediated LPS stimulation of IL-1Ra expression. Both IFN-gamma and IL-4 reversed the inhibitory effect of glucocorticoids on IL-1Ra expression and secretion. The effect of IFN-gamma was blocked by pretreatment of monocytes with an anti-IL-1beta blocking antibody, whereas the effect of IL-4 could not be blocked, demonstrating that IFN-gamma acts through a mechanism dependent on endogenous IL-1 production, whereas IL-4 acts through an IL-1-independent one. Consistent with this finding, IFN-gamma (but not IL-4) failed to reverse the inhibitory effect of glucocorticoids when stimulated by IL-1, and only IL-4 combined with IL-1 showed synergism resulting in an increase in IL-1 Ra production. The differential regulation and involvement of IL-1 in the expression of IL-1Ra by IFN-gamma, IL-4 and glucocorticoids sets the level of monocyte responsiveness during the Th1 or Th2 responses.

Glucocorticoids↗

PubMed1998

[The Munich Vulnerability Study of Affective Disorders. Overview of the results at index study].

The neurobiological alterations commonly found in affective disorders (e.g., alterations in the nocturnal sleep profile, dysfunction of the hypothalamic-pituitary-adrenocortical system) gradually recover with improvement of the depressive syndrome. Their persistence during full clinical remission, however, is associated with an increased risk for relapse and, thus may represent trait markers for affective disorders. In order to test this hypothesis, we designed a prospective study in which healthy first-degree relatives (high-risk probands; HRPs; n = 54) of patients with an affective disorder are investigated by means of polysomnography, the combined dexamethasone and corticotropine-releasing hormone (DEX-CRH) test and a variety of psychometric scales. In the present part of the study (index assessment), these HRPs, as a group, showed depression-like alterations in both the sleep pattern and the DEX-CRH-test outcome; furthermore, their psychometric profile was characterized by elevated scores on the scales assessing "rigidity" and "autonomic lability". On a single-case level, 35% of the HRPs were identified as conspicuous (depression-like) in at least two of the three areas investigated. A decision of whether or not this "conspicuousness" indeed represents a trait marker for affective disorders can be reached when the follow-up part of the study has identified those HRPs with their respective premorbide status who have developed an affective disorder in the meantime.

Adolescent↗

PubMed1998

The pre-morbid psychometric profile is stable over time in subjects at high familial risk for affective disorders.

BACKGROUND: The pre-morbid personality profile 'autonomic lability' (e.g. elevated neuroticism, frequent somatic complaints and increased interpersonal sensitivity) is suggested to be an antecedent of major depression. Recently, we reported that the psychometric profile of healthy first-degree relatives of patients with an affective disorder (so-called high-risk probands; HRPs) was characterized by the personality trait 'rigidity' in association with 'autonomic lability' and speculated that such a profile might be a potential candidate for a true vulnerability marker for affective disorders. Because one major prerequisite for any valid vulnerability marker is its stability over time, we re-examined our HRPs about four years after index assessment. METHODS: Sixteen HRPs from the initial sample (n=54) participated in the follow-up investigation which, on average, took place 47 months after index assessment. All these HRPs had remained mentally healthy during the follow-up period. RESULTS: The psychometric profile was remarkably stable over the four-year period when considering the total group of the 16 HRPs. On an individual level, similar findings were obtained. Allowing a fluctuation within a narrowly defined 'band width', a constancy of the self-ratings was found in 75% of the HRPs, within a broader 'band width' this was the case in 88% of the HRPs. LIMITATIONS: The power of the present observations appears to be somewhat limited due to the still small sample size of HRPs re-investigated and the fact that the control probands were not yet re-examined. CONCLUSIONS: The present follow-up findings in 16 probands at high risk for an affective disorder indicate a sufficient stability of the psychometric profile over time, so that this requirement for a true vulnerability marker is fulfilled.

Adult↗

PubMed1998

Behavioural profiles of two Wistar rat lines selectively bred for high or low anxiety-related behaviour.

Over the past years, two breeding lines, derived originally from outbred Wistar rats, have been established that differ markedly and consistently in their anxiety-related behaviour in the elevated plus-maze. At the age of ten weeks, rats were tested once on the elevated plus-maze and the males and females displaying the most anxious and the least anxious behaviour were sib-mated to start a new generation of the high anxiety-related behaviour (HAB) and the low anxiety-related behaviour (LAB) lines, respectively. The resulting difference in emotionality between these two lines was also evident in an open field test and correlated with differences in the forced swim test. In the open field, the HAB rats tended to be less active and explored the central zone of the open field much less than the LAB animals. In the forced swim test, HAB rats started floating earlier, spent significantly more time in this immobile posture and struggled less than LAB rats. However, in an olfactory-cued social discrimination task there was no difference between male and female animals from either line. The overall performance in these various behavioural tests suggests that selective breeding has resulted in rat lines not only differing markedly in their innate anxiety-related behaviour in the plus-maze, but also in other stress-related behavioural performances, suggesting a close link between the emotional evaluation of a novel and stressful situation and an individual's coping strategy.

Animals↗

PubMed1998

Enhanced morphine-induced behavioural effects and dopamine release in the nucleus accumbens in a transgenic mouse model of impaired glucocorticoid (type II) receptor function: influence of long-term treatment with the antidepressant moclobemide.

In vivo microdialysis experiments were conducted in transgenic mice with impaired glucocorticoid receptor function resulting from expression of antisense directed against glucocorticoid receptor messenger RNA. Basal corticosterone and serotonin levels in the nucleus accumbens of untreated transgenic mice were enhanced compared to control mice (B6C3F1). Following a systemic morphine injection (15 mg/kg) mesolimbic dopamine and serotonin release was markedly increased in transgenic mice compared to control mice and in parallel enhanced behavioural stimulation was observed in these animals. After pretreatment with the antidepressant moclobemide over a time period of eight weeks (15 mg/kg/day) elevated basal levels of both corticosterone and serotonin were normalized in transgenic mice. Furthermore, morphine-induced dopamine and serotonin release as well as behavioral stimulation were suppressed in transgenic mice and similar to that in control mice. The results indicate that impaired glucocorticoid receptor function influences the basal release of serotonin in the nucleus accumbens. This alteration has no effect on basal but on morphine-stimulated release of dopamine in the mesolimbic system. An enhanced sensitivity to the effects of morphine is apparently related to elevated brain corticosterone and serotonin levels and can be normalized by long-term antidepressant treatment.

Animals↗

PubMed1998

Corticotropin-releasing hormone receptor (type I) antisense targeting reduces anxiety.

Two brain-derived corticotropin-releasing hormone receptors have been cloned, termed corticotropin-releasing hormone receptors type I and type 2. Antisense oligodeoxynucleotides targeted to the cloned rat and mouse corticotropin-releasing hormone receptors type I messenger RNA reduced the binding of the natural ligand of the corticotropin-releasing hormone receptors type I and also the release of adenocorticotrophic hormone in primary rat anterior pituitary cells and in clonal mouse pituitary cells (AtT-20) by up to 60% in an application time-dependent manner. Studies on intracellular uptake of fluorescence-labelled oligodeoxynucleotides indicated a cytoplasmic accumulation starting within two to four hours after application of oligodeoxynucleotides in vitro. In vivo, antisense oligodeoxynucleotides infused intra-cerebroventricularly reduced binding of radiolabelled corticotropin-releasing hormone receptors in central sites of the rat brain. Anxiety induced by i.c.v. administration of corticotropin-releasing hormone was attenuated by corticotropin-releasing hormone receptors type I antisense treatment as determined in the elevated plus maze and in the novel open field test. The corticotropin-releasing hormone-induced behavioural changes were absent in corticotropin-releasing hormone receptors type I antisense-pretreated animals. These results show that the selected antisense probes used were able to suppress corticotropin-releasing hormone receptors type I function in vitro as well as in vivo and suggest that the development of drugs blocking this specific receptor might lead to a novel class of anxiolytics.

Adrenocorticotropic Hormone↗

PubMed1998

Dissociated central and peripheral release of vasopressin, but not oxytocin, in response to repeated swim stress: new insights into the secretory capacities of peptidergic neurons.

To investigate the effects of an ethologically-relevant stressor on central and peripheral release of arginine vasopressin and oxytocin, we forced adult male Wistar rats to swim for 10 min and simultaneously measured the release of the two peptides (i) within the hypothalamic supraoptic and paraventricular nuclei (by means of the microdialysis technique) and (ii) into the blood (by chronically-implanted jugular venous catheters). Forced swimming caused a significant rise in the release of arginine vasopressin and oxytocin within both the supraoptic nuclei (four-fold and three-fold, respectively) and the paraventricular nuclei (three-fold and four- to five-fold, respectively). Release patterns measured before, during and after repeated stress exposure on three consecutive days indicated that, at the level of the hypothalamus, the two neuropeptides are critically involved in the rats' stress response in a peptide-, locus- and stress-specific manner. Particularly, despite a general reduction of the recovery of the microdialysis probes over the time, the release of arginine vasopressin within the paraventricular nuclei and of oxytocin within the supraoptic nuclei tended to increase upon repeated stress exposure. Measurement of plasma peptide concentrations revealed that the central release of oxytocin was accompanied by a secretion of this peptide into the systemic circulation. In contrast, arginine vasopressin, assayed in the same plasma samples, failed to respond to the stressor. The latter finding is consistent with a dissociated release of the neuropeptide from different parts of a single neuron (soma/dendrites vs axon terminals). It provides evidence that under physiological conditions plasma hormone levels do not necessarily reflect the secretory activity of central components of the respective neuropeptidergic system.

Animals↗

PubMed1998

Increased basal activity of the hypothalamo-pituitary-adrenal axis during pregnancy in rats bred for high anxiety-related behaviour.

In order to test the hypothesis that prenatal hormones influence the emotional maturation of the offspring, the hypothalamo-pituitary-adrenal (HPA) axis activity was studied at the end of pregnancy in two rat breeding lines differing consistently in their innate anxiety-related behaviour in the elevated plus-maze. Virgin and pregnant rats were fitted with a chronic jugular vein catheter and tested 5 days later. The high basal level of anxiety-related behaviour (HAB) described in males and females of the HAB breeding line persists in pregnancy as indicated by a significantly reduced number of entries into and time spent on the open arms of the elevated plus-maze between days 18 and 20 of pregnancy compared with pregnant rats of the breeding line with low anxiety-related behaviour (LAB). In general, an increase in anxiety was found in both breeding lines in pregnancy compared with the respective virgin controls. With respect to HPA axis activity, increased basal levels of adrenocorticotropin (ACTH) and corticosterone have been found in pregnant rats of the HAB line compared with pregnant LAB rats. ACTH and corticosterone secretion in response to emotional and complex physical stressors (exposure to the elevated plus-maze and forced swimming, respectively) did not differ between virgin and pregnant rats of either breeding line. However, independent of the inborn emotionality of the animals, a general attenuation in the HPA axis response to stressors and to exogenous CRH could be confirmed in pregnant rats. The basal and stress-induced activity of the hypothalamo-neurohypophysial system secreting oxytocin and vasopressin was also tested, and no differences were found relating to the emotionality or reproductive state of the animals except for a reduced vasopressin secretion in pregnant HAB rats after forced swimming. The elevated basal activity of the HPA axis, including enhanced circulating concentrations of corticosterone in pregnant HAB rats, may influence both the neuroendocrine and emotional development of their offspring. Thus, the passing-on of maternal behavioural characteristics via prenatal, hormonal 'imprinting' has to be considered as a possible contribution to emotional maturation during an individual's development.

Adrenocorticotropic Hormone↗

PubMed1998

Hormonal response pattern in the combined DEX-CRH test is stable over time in subjects at high familial risk for affective disorders.

One of the major neurobiological alterations in depressive disorders consists in a disturbed regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. This is reflected by a pathological increase in the adrenocorticotropin (ACTH) and cortisol release after pretreatment with 1.5 mg dexamethasone (DEX) the previous night and a challenge with 100 micrograms corticotropin-releasing hormone (CRH) the next day. The changes evoked by this combined DEX-CRH test recede partially with an improvement of the psychopathological symptoms of depressed patients. It is still unclear, however, whether this long-lasting disturbance of the HPA system is due to acquired changes in the acute illness or whether it plays a causal role and could be considered as a trait or vulnerability marker for depression. In a previous study we have examined the HPA function of healthy probands with a high genetic load for affective disorders. We found that this group of high-risk probands (HRPs) showed abnormal DEX-CRH test results with a cortisol release that was between that of a control group and a group of patients with depression. In a follow-up study we now reexamined 14 of the 47 HRPs about 4 years after the index investigation and found surprisingly constant DEX-CRH test results, so that one of the requirements for a vulnerability marker is fulfilled.

Adrenocorticotropic Hormone↗