Search PubMed⌕ Search

Biomedical subjects

F Holsboer

Publications and source records attributed to F Holsboer.

At least 19 recordsLinked to original sources
PubMed2006

Differential disinhibition of the neonatal hypothalamic- pituitary-adrenal axis in brain-specific CRH receptor 1-knockout mice.

In the adult, corticotropin-releasing hormone (CRH) is the key mediator for the behavioural and neuroendocrine response to stress. It has also been hypothesized that, during postnatal development of the stress system, CRH controls the activity of the HPA axis and mediates the effects of early disturbances, e.g. 24 h of maternal deprivation. In the current study we investigated the function of specific brain corticotropin-releasing hormone receptor type 1 (CRHR1) subpopulations in the control of the HPA axis during postnatal development under basal conditions as well as after 24 h of maternal deprivation. We used two conditional CRHR1-deficient mouse lines which lack this receptor, either specifically in forebrain and limbic structures (Cam-CRHR1) or in all neurons (Nes-CRHR1). Basal circulating corticosterone was increased in Nes-CRHR1 mice compared to controls. Corticosterone response to maternal deprivation was significantly increased in both CRHR1-deficient lines. In the paraventricular nucleus, Cam-CRHR1 animals displayed enhanced CRH and decreased vasopressin expression levels. In contrast, gene expression in Nes-CRHR1 pups was strikingly similar to that in maternally deprived control pups. Furthermore, maternal deprivation resulted in an enhanced response of Cam-CRHR1 pups in the brain, while expression levels in Nes-CRHR1 mouse pups were mostly unchanged. Our results demonstrate that brainstem and/or hypothalamic CRHR1 contribute to the suppression of basal corticosterone secretion in the neonate, while limbic and/or forebrain CRHR1 dampen the activation of the neonatal HPA axis induced by maternal deprivation.

Animals↗
PubMed2006

Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism.

Angiotensin-converting enzyme (ACE) is assumed to influence the activity of the hypothalamic-pituitary-adrenocortical (HPA) system, which shows hyperactivity in the majority of patients with major depression. The ACE gene, known to be associated with cardiovascular disorders, which in turn are accompanied with an increased susceptibility for depression, is therefore a promising candidate gene for affective disorders. We investigated the genetic association between 35 single-nucleotide polymorphisms (SNPs) and an insertion/deletion (I/D)-polymorphism in the ACE gene and the susceptibility for unipolar major depression together with the genetic association with ACE serum activity and functional parameters of the HPA system. Two independent case/control samples with a total of 843 unrelated unipolar depressed patients and 1479 healthy controls were investigated. A case/control sample was screened to detect genetic associations with unipolar major depression. In addition, a replication sample was used to confirm the detected associations and to further investigate functional consequences of the genetic variants associated with depression. In the screening sample, two SNPs within the ACE gene were significantly associated with unipolar major depression. The association with unipolar major depression of one SNP (rs4291) located in the promoter region of the ACE gene was confirmed in our replication sample. The T-allele of this SNP was associated with depression and depressed T-allele carriers showed higher ACE serum activity and HPA-axis hyperactivity. Variants of the ACE gene such as SNP rs4291 are suggested susceptibility factors for unipolar major depression. We could show that SNP rs4291 influences ACE activity and HPA-axis hyperactivity and might therefore represent a common pathophysiologic link for unipolar depression and cardiovascular disease.

Adult↗
PubMed2006

Low doses of dexamethasone affect immune parameters in the absence of immunological stimulation.

Recent findings suggest an important role of subtle changes in the plasma levels of inflammatory cytokines within the brain-immune interplay. It is unclear how such changes are regulated in the absence of acute inflammatory or infectious stimuli. Endocrine systems are a good candidate, because innate immunity and the hypothalamo-pituitary-adrenal (HPA)-system are closely related: glucocorticoids have immunosuppressive properties and modulate cytokine release from stimulated mononuclear blood cells in vitro and the immune response in vivo, but it still remains unclear, whether they also modulate circulating cytokine levels in the absence of immunological stimuli. We measured the influence of 1.5 or 3.0 mg dexamethasone (DEX) per os at 09:00 or 21:00 hours on body temperature, cortisol plasma levels, differential white blood cell counts, and cytokine plasma levels in 40 healthy male volunteers using a double-blind, placebo-controlled study design. In addition to significant morning-evening differences in tympanic temperature and several immune parameters, we found that DEX-intake significantly increased tympanic temperature, decreased cortisol plasma levels, altered differential white blood cell counts and induced changes in unstimulated plasma cytokine levels. Whereas the levels of TNF-alpha and sTNF-R p75 were reduced, the levels of sTNF-R p55 increased after a transient decrease.

Administration, Oral↗
PubMed2006

Metabolic signals modulate hypothalamic-pituitary-adrenal axis activation during maternal separation of the neonatal mouse.

The postnatal development of the mouse is characterised by a period of hypo-responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to moderate stressors. Maternal separation disinhibits this blockade of the HPA axis, but the mechanism responsible is not clear. The present study examined the influence of metabolic signals on the central and peripheral components of the HPA axis in neonatal mice aged 8 days in absence or presence of the mother. Reductions in plasma glucose and leptin as well as rapid increases in plasma ghrelin were apparent in the neonate 4 h following maternal deprivation and maximal at 8 h. In addition, maternal separation induced an increase of neuropeptide Y (NPY) mRNA expression in the arcuate nucleus, a decrease of corticotrophin-releasing hormone (CRH) mRNA expression in the paraventricular nucleus and a rise in serum corticosterone. Pharmacological manipulation of the metabolic signals attenuated the HPA response to maternal separation. Thus, the rise in plasma corticosterone induced by maternal separation was ameliorated by prevention of reduction in blood glucose or blockade of the ghrelin signalling pathway, as were the hypothalamic changes in NPY and CRH mRNAs. By contrast, leptin treatment did not affect the HPA axis response to maternal separation. Together these results suggest that metabolic signals play an important role in triggering the HPA response of the neonate to maternal separation.

Analysis of Variance↗
PubMed2006

Growth hormone-releasing hormone and corticotropin-releasing hormone enhance non-rapid-eye-movement sleep after sleep deprivation.

The neuropeptides growth hormone (GH)-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH) regulate sleep and nocturnal hormone secretion in a reciprocal fashion, at least in males. GHRH promotes sleep and GH and inhibits hypothalamo-pituitary-adrenocortical (HPA) hormones. CRH exerts opposite effects. In women, a sexual dimorphism was found because GHRH impairs sleep and stimulates HPA hormones. Sleep deprivation (SD) is the most powerful stimulus for inducing sleep. Studies in rodents show a key role of GHRH in sleep promotion after SD. The effects of GHRH and CRH on sleep-endocrine activity during the recovery night after SD are unknown. We compared sleep EEG, GH, and cortisol secretion between nights before and after 40 h of SD in 48 normal women and men aged 19-67 yr. During the recovery night, GHRH, CRH, or placebo were injected repetitively. After placebo during the recovery night, non-rapid-eye-movement sleep (NREMS) and rapid-eye-movement sleep (REMS) increased and wakefulness decreased compared with the baseline night. After GHRH, the increase of NREMS and the decrease of wakefulness were more distinct than after placebo. Also, after CRH, NREMS increased higher than after placebo, and a positive correlation was found between age and the baseline-related increase of slow-wave sleep. REMS increased after placebo and after GHRH, but not after CRH. EEG spectral analysis showed increases in the lower frequencies and decreases in the higher frequencies during NREMS after each of the treatments. Cortisol and GH did not differ between baseline and recovery nights after placebo. After GHRH, GH increased and cortisol decreased. Cortisol increased after CRH. No sex differences were found in these changes. Our data suggest that GHRH and CRH augment NREMS promotion after SD. Marked differences appear to exist in peptidergic sleep regulation between spontaneous and recovery sleep.

Adult↗
PubMed2005

Brain activation and hypothalamic functional connectivity during human non-rapid eye movement sleep: an EEG/fMRI study.

Regional differences in sleep EEG dynamics indicate that sleep-related brain activity involves local brain processes with sleep stage specific activity patterns of neuronal populations. Macroscopically, it is not fully understood which cerebral brain regions are involved in the successive discontinuation of wakefulness. We simultaneously used EEG and functional MRI on 9 subjects (6 female: mean = 24.1 years, 3 male: mean = 26.0 years) and analyzed local blood oxygenation level dependent signal changes linked to the transition from wakefulness to different non-rapid eye movement (NREM) sleep stages (according to Rechtschaffen and Kales) of the first sleep cycles after 36 h of total sleep deprivation. Several brain regions throughout the cortex, the limbic lobe, the thalamus, the caudate nucleus, as well as midbrain structures, such as the mammillary body/hypothalamus, showed reduced activity during NREM sleep across all sleep stages. Additionally, we found deactivation patterns specific to NREM sleep stages compared with wakefulness suggesting that a synchronized sleeping state can be established only if these regions interact in a well-balanced way. Sleep stage 2, which is usually linked to the loss of self-conscious awareness, is associated with signal decreases comprising thalamic and hypothalamic regions, the cingulate cortex, the right insula and adjacent regions of the temporal lobe, the inferior parietal lobule and the inferior/middle frontal gyri. The hypothalamic region known to be of particular importance in the regulation of the sleep-wake cycle shows specific temporally correlated network activity with the cortex while the system is in the sleeping state, but not during wakefulness. We describe a specific pattern of decreased brain activity during sleep and suggest that this pattern must be synchronized for establishing and maintaining sleep.

Adult↗
PubMed2005

Pharmacogenomics.

So far no pharmacogenetic/genomic study has been conducted specifically for anxiety disorders. Some of the presented results, however, do pertain to such disorders. For example, pharmacokinetic aspects of antidepressant drug therapy likely also apply to patients with anxiety disorders, and several genetic polymorphisms in the cytochrome P450 (CYP) gene family and drug transporter molecules, such as the multidrug resistance (MDR) gene type 1, have been reported to influence the pharmacokinetics of antidepressant drugs. At this stage of pharmacogenomics research, it is difficult to interpret the relevance of pharmacodynamic-genetic association studies conducted in depressed patients for anxiety disorders. A number of studies have reported an influence of polymorphisms of genes mostly in the serotonergic pathway on the response to antidepressant drugs in patients suffering from depression. In order to know whether they can be extrapolated to patients with anxiety disorders, clinical studies are warranted. Despite all the shortcomings of the currently available pharmacogenetic studies, this field holds great promise for the treatment of anxiety disorders. In the future, psychiatrists may be able to base treatment decisions (i.e., the type and dose of prescribed drug) on more objective parameters than only the diagnostic algorithms used now. This will limit unwanted side effects and adverse drug reactions, and could reduce time to response, resulting in a more individualized pharmacotherapy.

Cytochrome P-450 Enzyme System↗
PubMed2005

Endocrine disturbances in depression.

Depression is one of the most common psychiatric disorders. For a long time, clinicians suspected a causal link between depression and the endocrine system. The most frequently occurring endocrine abnormality in depressed subjects is hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. CRH and AVP are likely to play a substantial role in the pathophysiology of this disorder, and their receptors appear to be a specific target for future antidepressant drugs. Depression also affects the hypothalamic-pituitary-GH (HPGH) and -thyroid (HPT) axes. Alterations in the reproductive system may also play a role in the pathology of depression. In addition, there is increasing evidence that leptin and neurosteroids, such as DHEA, are implicated in mood disorders.

Depressive Disorder↗
PubMed2005

"Anxietas tibiarum". Depression and anxiety disorders in patients with restless legs syndrome.

BACKGROUND: Symptoms of anxiety and depression in patients with restless legs syndrome (RLS) have been observed. However, it is unclear whether rates of threshold depression and anxiety disorders according to DSM-IV criteria in such patients are also elevated. METHODS: 238 RLS patients were assessed with a standardized diagnostic interview (Munich-Composite International Diagnostic Interview for DSM-IV) validated for subjects aged 18-65 years. Rates of anxiety and depressive disorders were compared between 130 RLS patients within this age range and 2265 community respondents from a nationally representative sample with somatic morbidity of other types. RESULTS: RLS patients revealed an increased risk of having 12-month anxiety and depressive disorders with particularly strong associations with panic disorder (OR=4.7; 95% CI=2.1-10.1), generalized anxiety disorder (OR=3.5; 95% CI= 1.7-7.1), and major depression (OR=2.6; 95% CI=1.5-4.4). In addition, lifetime rates of panic disorder and most depressive disorders as well as comorbid depression and anxiety disorders were considerably increased among RLS patients compared with controls. CONCLUSIONS: The results suggest that RLS patients are at increased risk of having specific anxiety and depressive disorders. Causal attributions of patients suggest that a considerable proportion of the excess morbidity for depression and panic disorder might be due to RLS symptomatology.

Adolescent↗
PubMed2005

The Munich vulnerability study on affective disorders: premorbid neuroendocrine profile of affected high-risk probands.

One of the most characteristic alterations in depression is a disturbed regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. A function test combining the pre-treatment of 1.5 mg dexamethasone (DEX) with a challenge of 100 microg corticotropin-releasing hormone (CRH) reveals a pathological increase in the adrenocorticotropin and cortisol release in patients with major depression. These changes partially persist after successful treatment with remission and therefore, might represent trait or vulnerability markers. To further address this question, we were investigating the premorbid neuroendocrine profile of 74 healthy high-risk probands (HRPs) with a positive family history for affective disorders. The aim was to identify premorbid vulnerability factors. During the observation period, 19 HRPs developed an affective disorder. Their premorbid DEX/CRH test results were compared with 19 age- and sex matched controls. No significant differences could be observed between these two groups. Our results suggest that a dysregulated HPA system indicated by this function test can rather be regarded as a neurobiological scar developing during the course of affective disorders.

Adult↗
PubMed2005

Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation.

An important question arising from previous observations in vivo is whether glucocorticoids can directly influence neuronal survival in the hippocampus. To this end, a primary postnatal hippocampal culture system containing mature neurons and expressing both glucocorticoid (GR) and mineralocorticoid (MR) receptors was developed. Results show that the GR agonist dexamethasone (DEX) targets neurons (microtubule-associated protein 2-positive cells) for death through apoptosis. GR-mediated cell death was counteracted by the MR agonist aldosterone (ALDO). Antagonism of MR with spironolactone ([7alpha-(acetylthio)-3-oxo-17alpha-pregn-4-ene-21 carbolactone] (SPIRO)) causes a dose-dependent increase in neuronal apoptosis in the absence of DEX, indicating that nanomolar levels of corticosterone present in the culture medium, which are sufficient to activate MR, can mask the apoptotic response to DEX. Indeed, both SPIRO and another MR antagonist, oxprenoate potassium ((7alpha,17alpha)-17-hydroxy-3-oxo-7-propylpregn-4-ene-21-carboxylic acid, potassium salt (RU28318)), accentuated DEX-induced apoptosis. These results demonstrate that GRs can act directly to induce hippocampal neuronal death and that demonstration of their full apoptotic potency depends on abolition of survival-promoting actions mediated by MR.

Animals↗
PubMed2004

Glucocorticoid receptor blockade disinhibits pituitary-adrenal activity during the stress hyporesponsive period of the mouse.

During postnatal development, mice undergo a period of reduced responsiveness of the pituitary-adrenal axis, the stress hyporesponsive period (SHRP), which is largely under control of maternal signals. The present study was designed to test the hypothesis that this quiescence in hypothalamic-pituitary-adrenal (HPA) activity is mediated by glucocorticoid feedback. For this purpose, the role of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) in control of HPA activity was examined during the SHRP and in response to 24 h of maternal deprivation. Nondeprived or deprived (24 h) CD1 mice on postnatal d 8 were injected sc at 16 and 8 h before testing with the MR antagonist RU28318 or the GR antagonist RU38486. The results showed that, in nondeprived mice, blockade of GR rather than MR triggered a profound increase in anterior pituitary proopiomelanocortin mRNA, circulating ACTH, and corticosterone concentrations. In contrast, CRH mRNA in hypothalamus and GR mRNA in hippocampus and hypothalamus were decreased. Blockade of the GR during the deprivation period amplified the rise in corticosterone induced by maternal deprivation, whereas it reversed the deprivation effect on the other HPA markers, leading to profound increases in plasma ACTH, proopiomelanocortin mRNA expression in the anterior pituitary, CRH mRNA expression in the paraventricular nucleus, and MR mRNA expression in the hippocampus, but not in GR mRNA expression in the hippocampus and paraventricular nucleus. In conclusion, the data suggest that control of postnatal pituitary-adrenal activity during the SHRP involves GR-mediated feedback in the anterior pituitary, which is further potentiated in the absence of the mother.

Adrenal Glands↗
PubMed2004

The effect of growth hormone substitution on cognitive performance in adult patients with hypopituitarism.

OBJECTIVE: Adult hypopituitary patients with growth hormone deficiency, though on adequate adrenal, thyroid or sex hormone replacement therapy, complain of attention and memory disabilities. During the past years several studies have evidenced that growth hormone (GH) may exert distinctive effects on the central nervous system and induce beneficial effects on psychological capabilities. The aim of our study was to determine whether a long-term replacement therapy of recombinant human growth hormone (rhGH) affects cognitive performance in adults with GH deficiency. DESIGN: A double-blind, randomized placebo controlled trial over 6 months, followed by an open period of 6 months of rhGH treatment. MEASUREMENTS: The assessment of cognitive performance comprised attention, verbal memory and non-verbal intelligence and was examined at baseline (0), at 3, 6, 9, and 12 months. In addition, emotional well-being and energy were assessed using the Nottingham Health Profile self rating questionnaire. PATIENTS: Eighteen hypopituitary patients, mean age 41.6 (range 21-63) years with adult onset GH deficiency were evaluated. Patients were on adequate and stable adrenal, thyroid, gonadal and desmopressin replacement therapy where necessary, but not substituted for GH deficiency. RESULTS: After 3 and 6 months of rhGH treatment in the closed label phase a significant improvement of attentional performance was observed compared to baseline in the rhGH group but not in the placebo group. After 6 months scores of attention were significantly different between rhGH and placebo treatment for the digit cancellation test and marginally different for the trail-making test. In contrast, long-term verbal memory and non-verbal intelligence did not improve compared to baseline during therapy and short-term memory improved both in the GH and the placebo group after 3 and 6 months. This was considered as a placebo or practice effect. In the open-label phase a further improvement of attention was found in the GH group and subsequent treatment with rhGH for 3 and 6 months in the placebo group also significantly improved attentional performance supporting the results of the rhGH group in the first 6 months of the double-blind phase. CONCLUSION: RhGH treatment appears to have a beneficial effect on attentional performance in adult hypopituitary patients with GH deficiency when treated for at least 3 months. Our study does not support a role for GH in influencing verbal memory or non-verbal intelligence.

Adult↗
PubMed2004

Impaired divided attention predicts delayed response and risk to relapse in subjects with depressive disorders.

BACKGROUND: This study addresses the complex relationship between cognitive function and the course of depression. METHOD: A sample of patients (n=73) in a depressive episode (major depression or bipolar disorder) was tested with a comprehensive battery of attention and executive tasks at both admission and discharge. In addition, response to pharmacological treatment and remission was assessed with standardized rating scales. Nineteen patients, recovered from depression, were re-investigated 6 months after discharge to determine whether specific cognitive parameters were related to subsequent relapse. RESULTS: On admission, patients were impaired in almost all cognitive tasks. At discharge, we found a significant reduction in psychopathology, but only marginal cognitive improvements. Non-responders after 4 weeks of antidepressive medication and subjects who did not achieve remission prior to discharge were specifically impaired in divided attention on admission (p < 0.05). In addition, a trend was found for the association between impaired divided attention at discharge and an elevated risk to relapse (p < 0.10). CONCLUSIONS: We observed generalized cognitive impairment in most cognitive domains in acute depression. Cognitive impairments were still within abnormal ranges at discharge but less distinct. Divided attention performance predicted response to treatment, remission of symptoms, and risk to relapse. Impaired divided attention capacity can be explained either by reduced attentional resources or impaired activation and/or top-down control of attentional resources by the central executive.

Acute Disease↗
PubMed2004

Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner.

The serotonin type 3 (5-HT(3)) receptor is the only ligand-gated ion channel receptor for serotonin (5-HT). 5-HT(3) receptors play an important role in modulating the inhibitory action of dopamine in mesocorticolimbic brain regions. Neuroleptic drugs are commonly thought to exert their psychopharmacological action mainly through dopamine and serotonin type 2 (5-HT(2)) receptors. Except for clozapine, a direct pharmacological interaction of neuroleptics with 5-HT(3) receptors has not yet been described. Using the concentration-clamp technique, we investigated the effects of flupentixol, various phenothiazines, haloperidol, clozapine and risperidone on Na(+)-inward currents through 5-HT(3) receptors stably expressed in human embryonic kidney 293 cells, and through endogenous 5-HT(3) receptors of murine N1E-115 neuroblastoma cells. In addition, we studied their effects on Ca(2+) influx, measured as a change in intracellular Ca(2+) concentrations ([Ca(2+)](i)). All neuroleptic drugs, but not risperidone, antagonized Na(+)- and Ca(2+)-inward currents evoked by 5-HT (10 microM for 2 s and 1 microM, respectively) in a voltage-independent manner. Only clozapine was a competitive antagonist, while all other compounds turned out to be noncompetitive. Fluphenazine and haloperidol affected membrane anisotropy at concentrations below their IC(50) values, indicating that a change in membrane anisotropy might contribute to their antagonistic effect at the 5-HT(3) receptor. Only structure analogues of flupentixol and fluphenazine with a lipophilic side chain were potent antagonists against 5-HT-evoked Na(+) and Ca(2+) currents. Since 5-HT(3) receptors modulate mesolimbic and mesocortical dopaminergic activity, the functional antagonism of neuroleptics at 5-HT(3) receptors may contribute to their antipsychotic efficacy and may constitute a not yet recognized pharmacological principle of these drugs.

Animals↗
PubMed2004

Hypothalamic-pituitary-adrenal system regulation in recently detoxified alcoholics is not altered by one week of treatment with acamprosate.

BACKGROUND: Acamprosate decreases relapse rates in alcohol-dependent patients by approximately 10-20% within the first year after detoxification. Psychological stress is a major risk fac-tor for relapse and is associated with activation of the hypothalamic-pituitary-adrenocortical (HPA) system. In recently detoxified alcoholics, the HPA system is dysregulated with non-suppression of cortisol after dexamethasone administration. We therefore investigated whether acamprosate normalizes HPA hyperactivity in alcoholics within the first 3 weeks of abstinence, employing a combined dexamethasone/corticotropin-releasing hormone (Dex-CRH)-test. METHODS: Thirty alcohol-dependent patients were tested one week after withdrawal signs had disappeared. In 15 patients, acamprosate, 1332-1998 mg/day, was administered orally and a second Dex-CRH test was performed 1 week later. In the other 15 patients, acamprosate treatment was offered only after the second test. RESULTS: CRH-stimulated cortisol secretion was significantly increased in both the acamprosate group and the group receiving no anti-relapse medication compared to a control group of 15 healthy subjects. Acamprosate treatment had no effect on basal or CRH-stimulated ACTH or cortisol secretion. CONCLUSIONS: We conclude that 1 week of acamprosate treatment does not attenuate the HPA dysregulation ob-served during early abstinence.

Acamprosate↗
PubMed2004

The Munich vulnerability study on affective disorders: premorbid psychometric profile of affected individuals.

OBJECTIVE: We conducted a longitudinal high-risk study to identify psychometric vulnerability markers for affective disorders. METHOD: We examined 82 healthy subjects [high-risk probands (HRPs)] with at least one first-degree relative suffering from an affective disorder. The premorbid psychometric profile of 20 HRPs who developed a psychiatric disorder during follow-up was compared with the profile of control subjects without personal and family history of psychiatric disorders matched for age and gender. RESULTS: Somatization, complaints (vegetative lability), and perception of strain are increased in HRPs who developed a psychiatric disorder. These alterations were not influenced by the time interval until the onset of the disorder. CONCLUSION: The premorbid psychometric profile in subjects at high risk for affective disorders is characterized by somatization, complaints, and elevated perception of strain. Together with previous findings our results suggest that these alterations can be regarded as potential vulnerability markers for affective disorders.

Adaptation, Psychological↗