Norbert Wodarz

Normal lymphocyte responsiveness to lectins but impaired sensitivity to in vitro glucocorticoids in major depression

The mitogen-induced lymphocyte proliferative response and its sensitivity to in vitro (10(-10)-10(-6) M) dexamethasone (DEX) administration were investigated in 12 severely depressed patients and 13 healthy controls. Patients with major depressive disorder exhibited no impairment of lectin-induced blastogenesis, but a significantly weaker suppressive effect of in vitro DEX on 1.0 microgram/ml phytohemagglutinin A-induced proliferation. The inhibitory potency of in vitro DEX was inversely correlated with in vivo adrenal cortical hormone levels at 4.00 p.m. These effects were not observed with pokeweed mitogen- and concanavalin A-stimulated cells. There were no correlations with age, weight, sex or severity of depression. These results do not support the hypothesis of a primarily impaired cell-mediated immunity, but might be indicative of reduced glucocorticoid receptor sensitivity in major depressive disorder.

Disturbed glucocorticoid receptor autoregulation and corticotropin response to dexamethasone in depressives pretreated with metyrapone

We studied glucocorticoid receptor autoregulation and corticotropin response to dexamethasone in depressed patients and controls, attempting to control for the confounding effect of endogenous glucocorticoids. After depletion of endogenous cortisol, depressed patients showed an attenuated suppressibility of corticotropin by dexamethasone in the face of unchanged dexamethasone plasma levels. Beta-endorphin levels were strongly correlated with adrenocorticotropic hormone (ACTH) concentrations. Although metyrapone administration resulted in a marked rise of glucocorticoid receptor sites per cell in controls, this effect was not present in depressives. These data support the hypothesis of a decreased glucocorticoid receptor plasticity and a partial steroid resistance in depression.

Sensation seeking, alcoholism and dopamine activity

Sensation seeking scale (SSS) scores were determined in 15 alcohol dependent men with a positive family history for alcoholism (FHP), in 15 alcohol dependent men with a negative family history for alcoholism (FHN) and in 15 well-matched healthy male controls (CONTR). Both FHPs and FHNs suffered from longlasting alcohol dependence meeting ICD-10 and DSM-III-R diagnostic criteria. Dopamine activity was neuroendocrinologically assessed by measuring the amount of growth hormone released after stimulation with the dopamine receptor agonist apomorphine. Planned comparisons within a one-way ANOVA yielded significantly elevated levels of boredom susceptibility (BOS) in both FHPs and FHNs against CONTRs. SSS total scores, while approaching statistical significance, were elevated in FHPs only. Partial correlations (controlling for age, body weight, alcohol intake and duration of dependence) were calculated to examine the relationship between SSS and dopamine activity. Among the SSS subtraits, BOS revealed the highest correlation in each group. However, only in CONTRs did the relationship between BOS and dopamine activity reach statistical significance.

Cell-mediated immunity and its glucocorticoid-sensitivity after clinical recovery from severe major depressive disorder

This follow-up study investigated lymphocyte blastogenesis induced by concanavalin A, phytohemagglutinin A, and pokeweed mitogen and their sensitivity to in vitro dexamethasone administration in 12 patients clinically recovered from severe major depression. Although cortisol-levels at 4.00 p.m. decreased significantly after clinical remission, mitogen-driven lymphocyte proliferative responses were unchanged when assessed intra-individually. No impairment of in vitro glucocorticoid-sensitivity of lectin-induced lymphocyte blastogenesis could be observed in clinically recovered patients. The inhibitory potency of in vitro dexamethasone was found to be inversely correlated with in vivo adrenal cortical hormone levels. There were no correlations with age, weight, sex, antidepressant medication, severity or duration of depression. No differences from age- and sex-matched healthy individuals were found. These results indicate that reduced glucocorticoid receptor sensitivity occurs only during the acute depressive illness.

In vivo and in vitro Effects of Glucocorticoids on Lymphocyte Proliferation in Man: Relationship to Glucocorticoid Receptors

Interrelations between the hypothalamic-pituitary-adrenal system (HPA) and the immune system represent a well-documented biological phenomenon. While in vitro administration of glucocorticoids may inhibit concanavalin A (Con A)- and phytohemagglutinin (PHA)-induced T-cell proliferation, pokeweed mitogen (PWM)-driven B-cell mitogenesis is relatively resistant to glucocorticoids. To further explore the link between the HPA and the immune system in relation to glucocorticoid receptor function, dose-response curves were obtained for Con A- and PHA-induced T-cell mitogenesis, PWM-generated B-cell mitogenesis and spontaneous lymphocyte proliferation in 13 healthy controls. Glucocorticoid effects were assessed in vivo by depletion of endogenous glucocorticoids after oral administration of 1.5 g metyrapone (MET) and subsequent glucocorticoid replacement, and in vitro by incubation of the cells with different doses of dexamethasone (DEX). There was a significant decrease in PWM-induced B-cell mitogenesis and a more pronounced effect of DEX administered in vitro on spontaneous lymphocyte proliferation after MET treatment when compared with the DEX plus MET pretreated condition in vivo. These data suggest that the inhibition of spontaneous lymphocyte proliferation by glucocorticoids in vitro is related to glucocorticoid receptor function. The decrease in PWM-generated B-cell proliferation following cortisol depletion by MET may be seen in connection with impaired glucocorticoid-mediated induction of interleukin-1 receptor synthesis.

A Functional Polymorphism in the Promoter Region of the Monoamine Oxidase A Gene Is Associated with the Cigarette Smoking Quantity in Alcohol-Dependent Heavy Smokers

Tobacco smoking represents a leading cause of morbidity and mortality with a strong dose-response relation between the amount of smoking and the risks of tobacco-related diseases and death. The quantity that is smoked is determined predominantly by genetic factors. The present study examined whether there is an association between the quantity of cigarettes smoked and length variation of a functional 30-bp repeat polymorphism in the promoter region of the monoamine oxidase A (MAO-A) gene. The number of 30-bp repeats, which is associated with enzyme activity was assessed in 121 Caucasian men suffering from both alcohol and tobacco dependence. Analysis revealed that the highly active long allele (4 repeat) is associated with a significantly greater amount of cigarette smoking in comparison with the less active short allele (3 repeat). In a logistic regression model (dichotomized), smoking quantity was significantly predicted by MAO-A genotype while no other variable (age, height, body weight, frequency of smoking, quantity and frequency of alcohol consumption) met the significance level. Since tobacco smoke is a potent inhibitor of MAO-A, this result could be regarded as a genotype-related dosage effect. Taken together, in alcohol-dependent heavily smoking men there is evidence for a MAO-A gene-associated effect on the quantity that is smoked as reflected by the daily number of cigarettes consumed.

Elevated Glucocorticoid Receptor Concentrations before and after Glucocorticoid Therapy in Peripheral Mononuclear Leukocytes of Patients with Atopic Dermatitis

The number and affinity of glucocorticoid binding sites in peripheral mononuclear leukocytes of patients with atopic dermatitis (AD) and healthy controls were determined under baseline conditions and after a defined oral glucocorticoid treatment. Patients with AD (n = 15) exhibited significantly more glucocorticoid receptors (GR) per cell than the control group (n = 22), while the GR affinity did not differ. Methylprednisolone treatment resulted in a significant reduction of the GR sites per cell in the steroid-treated control group (n = 10) in contrast to the patients. The dissociation constant was not affected by methylprednisolone treatment in either group. In view of the therapeutic efficiency of glucocorticoids in AD and findings of abnormal cAMP and cAMP-phosphodiesterase activity, the elevated GR concentrations in AD lend support to the hypothesis of a compensatory GR upregulation due to an insufficient action of endogenous cortisol or to altered cAMP-induced GR expression.

In vivo and in vitro effects of glucocorticoids on lymphocyte proliferation in depression

SummaryTwelve severely depressed patients and 13 healthy controls were studied under baseline, metyrapone and metyrapone plus dexamethasone pretreated conditions. Lymphocyte proliferation data were obatained by concanavalin A, phytohaemagglutinin and pokeweed mitogen (PWM) stimulation. There was a decrease in PWM-induced B-cell proliferatin and an increase in inhibition of spontaneous leucocyte proliferation by dexamethasone added in vitro following metyrapone administration in vivo, in healthy controls, which was not present in the depressed patients. These data support the concept of a decreased functional plasticity of the glucocorticoid receptor in depression also at the cellular level.

Lymphocyte glucocorticoid receptor binding during depression and after clinical recovery

Lymphocyte glucocorticoid receptor binding parameters were studied in 15 severely depressed patients during depression and after clinical recovery, and in 15 healthy controls. There was no difference in glucocorticoid receptor number or affinity between depressed patients and recovered or control subjects. Afternoon ACTH and cortisol concentrations did not differ significantly between the three groups. No relationship could be established between glucocorticoid receptor binding and antidepressant medication. These data support the view of an impaired ligand-induced plasticity of glucocorticoid receptor regulation rather than the hypothesis of decreased glucocorticoid receptor numbers during depression.

Characterization of Glucocorticoid Binding Capacity in Human Mononuclear Lymphocytes: Increase by Metyrapone is Prevented by Dexamethasone Pretreatment.

Autoregulation of receptor systems by their own ligands is a well established biological phenomenon. While down‐regulation of the glucocorticoid binding capacity by glucocorticoids has been shown in animals and humans, data on up‐regulation processes in humans are lacking. To further explore glucocorticoid receptor plasticity in relation to endogenous ligands, glucocorticoid binding parameters were assessed in 15 healthy controls before and after oral administration of 1.5 g metyrapone with and without dexamethasone pretreatment. Administration of metyrapone resulted in blockade of the feedback of the hypothalamic‐pituitary‐adrenal system as shown by the rise in adrenocorticotropin levels, while pretreatment with 1 mg dexamethasone completely suppressed adrenocorticotropin concentrations. Glucocorticoid binding sites per lymphocyte exhibited an increase of 63% following metyrapone administration, which was prevented by dexamethasone pretreatment. Comparison of morning and afternoon glucocorticoid binding sites per cell in 11 healthy volunteers further revealed a diurnal rhythm of glucocorticoid receptor sites. These data suggest that human lymphocyte glucocorticoid receptors are under autoregulatory control.