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A H Miller

Publications and source records attributed to A H Miller.

At least 37 records · Page 2Linked to original sources
PubMed1999

Effects of cytokines on glucocorticoid receptor expression and function. Glucocorticoid resistance and relevance to depression.

Our data indicate that the proinflammatory cytokine, IL-1alpha inhibits GR translocation and hormone-induced GR-mediated gene transcription, and, in conjunction with previous in vivo and in vitro studies, can be interpreted to suggest that cytokines have the capacity to contribute to glucocorticoid resistance and thus the pathophysiology of depression. In addition, data from our mouse viral studies in glucocorticoid deficient animals demonstrate that endogenous glucocorticoids modulate a delicate balance between viral defense and cytokine toxicity. Finally, the antidepressant, DMI, has been found to enhance GR translocation and GR-mediated gene transcription and thus may provide a useful strategy for adjusting neuroendocrine setpoints in vivo. Taken together, these findings suggest that factors which modulate glucocorticoid action (e.g. cytokines and antidepressants) will be relevant contributors to disease expression including behavioral toxicity and sickness behavior.

Animals↗
PubMed1999

The effects of neonatal stress on brain development: implications for psychopathology.

Recent studies have focused on the behavioral and neurobiological sequella of exposure to early adverse events. We hypothesize that early adverse experiences result in an increased sensitivity to the effects of stress later in life and render an individual vulnerable to stress-related psychiatric disorders. This vulnerability may be mediated by persistent changes in corticotropin-releasing-factor (CRF)-containing neurons, the hypothalamic-pituitary-adrenal axis, and the sympathetic nervous system. We therefore present an overview of the CRF system and its role as a mediator in the development of the stress response, major depression, and posttraumatic stress disorder. The literature pertaining to behavioral and neurobiological alterations associated with exposure to early adverse life events in rodents, nonhuman primates, and humans is reviewed. We focus on animal models that precipitate depressive and anxiety symptoms while producing neuroendocrine alterations that mimic those seen in adults with those disorders. The literature integrating neurobiological and behavioral consequences of early life stress is also reviewed, focusing primarily on infants born to mothers with depression and on infants who were abused or neglected.

Adult↗
PubMed1999

The proinflammatory cytokine, interleukin-1alpha, reduces glucocorticoid receptor translocation and function.

Proinflammatory cytokines have been shown to influence the expression and function of the glucocorticoid receptor (GR). Specifically, several studies have found that cytokines induce a decrease in GR function, as evidenced by reduced sensitivity to glucocorticoid effects on functional end points. To investigate the potential mechanism(s) involved, we examined the impact of the proinflammatory cytokine, interleukin-1alpha (IL-1alpha), on 1) GR translocation from cytoplasm to nucleus using GR immunostaining, 2) cytosolic radioligand GR binding, and 3) GR-mediated gene transcription in L929 cells stably transfected with the mouse mammary tumor virus-cholamphenicol acetyltransferase reporter gene. L929 cells were treated with IL-1alpha (100 and 1000 U/ml) for 24 h in the presence or absence of dexamethasone (Dex; 10 nM to 1 microM). IL-1alpha inhibited Dex-induced GR translocation and alone induced GR up-regulation. Pretreatment with IL-1alpha followed by Dex treatment for 1.5 h led to about 20% inhibition of Dex-induced GR-mediated gene transcription, whereas coincubation of IL-1alpha plus Dex for 24 h inhibited Dex-induced GR-mediated gene activity up to 42%. The latter effect was reversed by the IL-1 receptor antagonist. These results suggest that cytokines produced during an inflammatory response may induce GR resistance in relevant cell types by direct effects on the GR, thereby providing an additional pathway by which the immune system can influence the hypothalamic-pituitary-adrenal axis.

Animals↗
PubMed1999

Cerebrospinal fluid and plasma leptin measurements: covariability with dopamine and cortisol in fasting humans.

Leptin (OB protein) is an important signal in the regulation of energy balance. Leptin levels correlate with adiposity, but also decrease acutely with caloric restriction and increase with refeeding. The brain is an established critical site of leptin function, yet little is known about leptin concentrations in the central nervous system relative to plasma levels, psychiatric diagnoses, and other endocrine parameters. Therefore, using a novel ultrasensitive leptin assay, we explored relationships of human plasma and cerebrospinal fluid (CSF) leptin levels to body mass index, smoking, posttraumatic stress disorder diagnosis, and levels of dopamine, monoamine metabolites, beta-lipotropin, glucocorticoid, and thyroid and cytokine hormones. A strong linear relation between CSF and plasma leptin levels in the am (r = 0.63; P < 0.002) and afternoon (r = 0.90; P < 0.0001) was revealed. CSF and plasma leptin concentrations decreased during a 12- to 20-h period of fasting. A strong association was found between plasma leptin and CSF dopamine levels (r = 0.74; P < 0.01) as well as between CSF leptin levels and urinary free cortisol (r = 0.73; P < 0.01). Both of these parameters covaried with leptin independently of adiposity, as estimated by body mass index. Implications for leptin transport, regulation, and its potential role in therapeutic strategies for obesity and diabetes are discussed.

Adult↗
PubMed1998

Glucocorticoid receptors are differentially expressed in the cells and tissues of the immune system.

Cytosolic glucocorticoid receptor (GR) binding studies on immune tissues demonstrate that the thymus exhibits three to four times higher levels of GR protein than the spleen. High levels of GR are consistent with the exquisite sensitivity of the thymus to glucocorticoid exposure. Nevertheless, whole cell binding studies reveal similar levels of GR in immature thymic T lymphocytes and more mature, splenic T lymphocytes. Moreover, whole cell binding techniques indicate that neutrophils (which represent roughly 30% of splenic leukocytes) exhibit higher GR than both T and B lymphocytes, further contradicting results from cytosolic binding studies. To address these inconsistencies, GR protein was assessed in immune cells and tissues using cytosolic radioligand binding. Western blot analysis, and immunocytochemistry. Consistent with previous cytosolic receptor binding studies on immune tissue homogenates, thymic T cells were found to have higher levels of GR than T cells isolated from the spleen. In addition, neutrophils were found to have fewer GR than lymphocytes and monocytes. These results indicate a meaningful relationship between receptor expression and known sensitivity to glucocorticoids.

Animals↗
PubMed1998

Neuroendocrine and immune system interactions in stress and depression.

Based on the extensive characterization of communication pathways between the nervous system and the immune system, there has been increasing interest in the impact of the nervous system on the development and expression of disorders involving the immune system and the contribution of the immune system to psychiatric disease. A vast literature has documented the impact of various stressors on a wide array of immune partners, and the specific neuroendocrine pathways involved have been elucidated. The impact of cytokines on neuroendocrine function and behavior has also been determined, and the relevance of cytokines to the pathophysiology of depression has become an exciting new research frontier. This article provides a foundation for integrating neuroendocrine-immune interactions into the formulation of neuropsychiatric and immunologic disease.

Depression↗
PubMed1997

Characterization of early cytokine responses and an interleukin (IL)-6-dependent pathway of endogenous glucocorticoid induction during murine cytomegalovirus infection.

Early infection with murine cytomegalovirus (MCMV) induces circulating levels of interleukin (IL)-12, interferon (IFN)-gamma, and tumor necrosis factor (TNF). Studies presented here further characterize these responses by defining kinetics and extending evaluation to include IL-1, IL-6, and glucocorticoids. IL-12 p40, IFN-gamma, TNF, IL-1alpha, and IL-6 were shown to be increased, but IL-1beta was undetectable, in serum of MCMV-infected mice. The IL-12 p40, IFN-gamma, TNF, and IL-6 responses were dramatic with peak levels reaching >150-10,000 pg/ml at 32-40 h after infection and rapidly declining thereafter. Glucocorticoid induction, peaking at 36 h and reaching 30-fold increases above control values, accompanied the cytokine responses. Mice with cytokine deficiencies or neutralized cytokine function demonstrated that IL-6 was the pivotal mediator of the glucocorticoid response, with IL-1 contributing to IL-6 production. The IL-6 requirement appeared to be specific for virus-type stimuli as the synthetic analogue of viral nucleic acid, polyinosinic-polycytidylic acid, also induced IL-6-dependent glucocorticoid release, but treatments with the bacterial product lipopolysaccharide and a non-immune physical restraint stressor elicited IL-6-independent responses. Collectively, the results identify IL-6 as a primary mediator of glucocorticoid induction, and elucidate specific pathways of interactions between immune and neuroendocrine systems during viral infection.

Adrenocorticotropic Hormone↗
PubMed1997

1996 Curt P. Richter Award. Effects of viral infection on corticosterone secretion and glucocorticoid receptor binding in immune tissues.

During an immune challenge it has been suggested that responding cells secrete cytokines which then stimulate the release of glucocorticoids. Glucocorticoids, in turn, are believed to bind to their receptors in target immune tissues and provide feedback inhibition on evolving immune responses. The foundations for this hypothesis have been drawn primarily from studies on animal models of autoimmune and/or inflammatory processes, and the relevance of these glucocorticoid-immune interactions to viral infections has not been extensively examined. Accordingly, we infected mice with lymphocytic choriomeningitis virus (LCMV) and measured plasma corticosterone and cytosolic glucocorticoid receptor (GR) binding at multiple time points throughout the day and throughout infection (days 3, 5, 7 and 10 post infection). Despite a vigorous immune response to this virus, LCMV infection was associated with minimal and transient increases in corticosterone secretion. Interestingly, however, significant decreases in cytosolic GR were found in immune tissues. Receptor decreases were characterized by a significant decrease in GR binding during the diurnal rise in corticosterone in the spleen and thymus of infected but not uninfected animals on days 5-10 post infection. In addition, in the morning on these days, GR binding in the spleen of infected mice was decreased compared to uninfected control mice. Following an acute injection of corticosterone on day 7 post infection, LCMV-infected animals exhibited a significantly greater decrease in splenic GR binding than uninfected control mice, suggesting an increased sensitivity to corticosterone in infected animals. No changes were found in the affinity (Kd) of the GR during infection, nor was there evidence of an infection-associated decrease in plasma corticosteroid binding globulin. The appearance of significant GR changes in the spleen and thymus, in the absence of significant elevations in corticosterone or decreases in its binding protein, suggests that cytokines and/or other factors produced within the immune tissues during infection either directly influenced GR number and/or function or influenced the local availability of corticosterone. Taken together, the results indicate that interactions between the neuroendocrine and immune systems can be modified at the level of the GR in the context of an ongoing immune response such as during a viral infection.

Adrenalectomy↗
PubMed1997

Steroid-independent translocation of the glucocorticoid receptor by the antidepressant desipramine.

The glucocorticoid receptor (GR) is a ligand-regulated transcription factor that in its unactivated form resides primarily in the cytoplasm. After being bound by steroid, the GR undergoes a conformational change and translocates to the nucleus, where it influences gene transcription. Because the GR mediates negative feedback exerted by circulating glucocorticoid hormones on the hypothalamic-pituitary-adrenal (HPA) axis, it has been hypothesized that abnormalities in GR expression and/or function may underlie the HPA axis hyperactivity described in patients with major depression. In further support of this hypothesis, animal studies have shown that long term in vivo treatment with antidepressants enhances glucocorticoid feedback inhibition, possibly through a direct effect on the GR. To examine this latter possibility, we evaluated translocation of the GR from the cytoplasm to the nucleus after 24-hr in vitro treatment of L929 cells (mouse fibroblasts) with the tricyclic antidepressant desipramine (0.1-10 microM) in the presence or absence of the synthetic steroid dexamethasone. In addition, GR-mediated gene transcription was measured with the use of L929 cells stably transfected with the mouse mammary tumor virus-chloramphenicol acetyltransferase reporter gene. Desipramine was found to (i) induce GR translocation from the cytoplasm to the nucleus in the absence of steroids (with no effect alone on GR-mediated gene transcription) and (ii) potentiate dexamethasone-induced GR translocation and dexamethasone-induced GR-mediated gene transcription. Treatment with desipramine for 24-96 hr had no effect on the expression of GR protein as measured by cytosolic radioligand receptor binding. We suggest that one important aspect of the effects of antidepressants in vivo may be to facilitate GR-mediated feedback inhibition on the HPA axis, by facilitating GR translocation and function, and thereby reverse glucocorticoid hypersecretion in depression.

Animals↗
PubMed1997

Chronic caregiving stress alters peripheral blood immune parameters: the role of age and severity of stress.

BACKGROUND: To examine the impact of chronic psychological stress on the immune system, a series of cellular and humoral immunological parameters was compared in 18 female caregivers of handicapped people and 18 age- and sexmatched controls. METHODS: The immunological parameters included assessment of T cell number (T cells, T helper, and T suppressor/cytotoxic) and function (delayed-type cutaneous hypersensitivity), antibody titers for latent herpesviruses (cytomegalovirus and herpes simplex virus 1 and 2), and markers of inflammation (complement C3 and C4 factors and c-reactive protein). Serum immunoglobulins (IgG, IgM, IgA, IgE) and titers for the nonlatent virus roseola were used to control for nonspecific elevations in serum proteins. Results were associated with the age of the investigated subjects, the severity of stress (family burden) and the degree of disability of the handicapped people. RESULTS: Caregivers had a significantly lower percentage of T cells, a significantly higher percentage of T suppressor/cytotoxic cells and a significantly lower T helper:suppressor ratio. Subjects were also analyzed after division into two groups according to the median age (45 years). Compared to their matched controls, older caregivers (mean age = 50.3) also had lower numbers of T cells and T helper cells and higher antibody titers for cytomegalovirus. In addition, in the caregiver population severity of stress was significantly positively correlated with T suppressor/cytotoxic cells and negatively correlated with T helper:suppressor ratio. No other differneces in the immune parameters were found between caregivers and controls. CONCLUSIONS: The results indicate that psychological stress differentially affects various aspects of the immune system and confirm the relevant role of age and severity of stress in modulating these influences.

Adult↗
PubMed1996

Stress-induced changes in blood leukocyte distribution. Role of adrenal steroid hormones.

The numbers and proportions of leukocytes in the blood provide an important representation of the state of activation of the immune system, and of the pattern of distribution of immune cells in the body. We have shown previously that acute stress induces large, rapid, and reversible changes in the distribution of peripheral blood leukocyte subpopulations in the rat. The studies described here specifically investigate the role played by adrenal steroid hormones in mediating stress-induced changes in blood leukocyte distribution. Since adrenal steroids act at two distinct receptor subtypes that show a heterogeneity of expression in immune cells and tissues, the role played by each subtype in mediating changes in leukocyte distribution is also investigated. Cyanoketone, a corticosterone (CORT) synthesis inhibitor, significantly reduced the decrease in lymphocyte numbers observed during stress and significantly enhanced the increase in neutrophil numbers observed after the cessation of stress. Acute administration of aldosterone (a specific type I adrenal steroid receptor agonist) to adrenalectomized animals did not have a significant effect on blood leukocyte numbers. In contrast, acute administration of CORT (the endogenous type I and type II receptor agonist), or RU28362 (a specific type II receptor agonist), to adrenalectomized animals produced changes in leukocyte distribution that were similar to those observed in intact animals during stress. These results suggest that CORT, acting at the type II adrenal steroid receptor, is a major mediator of the stress-induced changes in blood lymphocyte and monocyte distribution.

3-Hydroxysteroid Dehydrogenases↗
PubMed1996

Chronic social stress produces reductions in available splenic type II corticosteroid receptor binding and plasma corticosteroid binding globulin levels.

Adult male and female rats were housed for 2 weeks in a Visible Burrow System resulting in the development of strong dominant-subordinate relationships among the male rats. Neuroendocrine measures indicated that the subordinate rats, and to a lesser extent dominant rats, experienced chronic HPA axis hyperstimulation during the 2 week experience. This paper focuses on the consequences of this chronic social stress on cytosolic type II corticosteroid receptor binding in the spleen. In the first study, rats were adrenalectomized 18 h prior to sacrifice in order to measure total cellular receptor protein levels in each animal. In spite of the severity of the social stress, there was no decrease in splenic type II corticosteroid receptor binding levels in these short-term adrenalectomized animals. In the second study, rats were left adrenal-intact. Corticosteroid receptor levels in these adrenal-intact animals reflect the level of receptors (available receptors) that were unoccupied by endogenous hormone at the time of sacrifice. Both subordinate and dominant rats had fewer available splenic type II receptors than control rats, suggesting that a greater proportion of receptors in subordinate and dominant rats were occupied and activated by endogenous hormone at the time of sacrifice than in control rats. The differences in available receptor levels were not a function of total plasma corticosterone levels at the time of sacrifice (mean corticosterone levels were the same for control and subordinate rats). Instead, the differences in available receptor levels may have been a function of plasma corticosteroid binding globulin (CBG) levels which regulate free corticosterone levels. There was a large reduction in plasma CBG levels of subordinate (-70%) and dominant (-40%) rats relative to control rats, and there was a significant correlation between plasma CBG level and available type II receptors in the spleen. These results suggest that a decrease in CBG levels as a result of chronic social stress led to greater access of free corticosterone hormone to type II receptors in the spleen than is typically present in rats under basal or acute stress conditions. This result illustrates one mechanism by which chronic stress may have a greater impact than acute stress on splenic immune function.

Animals↗
PubMed1995

Effects of stress on immune cell distribution. Dynamics and hormonal mechanisms.

Immune cell trafficking is crucial to the performance of the surveillance as well as effector functions of the immune system. Because immune cells travel between tissues through the bloodstream, the numbers and proportions of leukocytes in the circulation provide an important representation of the state of leukocyte distribution in the body. The studies described here examine significant and selective changes in numbers and percentages of peripheral blood leukocyte subpopulations in the rat. These changes were rapidly induced under conditions of mild acute stress. Stress-induced increases in plasma corticosterone were accompanied by a significant decrease in numbers and percentages of lymphocytes, and by an increase in numbers and percentages of neutrophils. flow cytometric analysis revealed that B cell, NK cell, and monocyte numbers showed a greater stress-induced decrease than did T cells. All stress-induced changes were observed during the light (inactive) as well as the dark (active) period of the animal's diurnal cycle. Importantly, the stress-induced changes in leukocyte numbers and percentages were rapidly reversed upon the cessation of stress. Furthermore, the effects of stress were largely dependent on adrenal hormones, because the magnitude of the stress-induced changes was significantly reduced in adrenalectomized animals. Moreover, administration of corticosterone to adrenalectomized animals resulted in a close replication of stress-induced changes observed in adrenal-intact animals. These results suggest that endocrine factors released during stress modulate leukocyte trafficking and result in the redistribution of leukocytes between the blood and other immune compartments. Such a redistribution may significantly affect the ability of the immune system to respond to potential or ongoing immune challenge.

Adrenal Glands↗
PubMed1995

Mechanism of interleukin 12-mediated toxicities during experimental viral infections: role of tumor necrosis factor and glucocorticoids.

Interleukin 12 (IL-12) doses in excess of 100 ng/d have been shown to induce profound immunotoxicities in mice infected with lymphocytic choriomeningitis virus (LCMV). These immunotoxicities are characterized by almost complete inhibition of virus-induced CD8+ T cell expansion and CTL activation, and up to 2 log increases in viral replication. They are accompanied by induction of serum tumor necrosis factor (TNF). The studies presented here were undertaken to characterize mechanisms for the IL-12-induced toxicities and to examine expression and function of TNF in this context. Several physiological changes were induced in IL-12-treated uninfected and dramatically elevated in IL-12-treated virus-infected mice. IL-12 induced (a) decreases in body weights, > 10% in uninfected and > 20% in LCMV-infected mice; (b) elevation of circulating glucocorticoid levels to > 10 micrograms/dl in uninfected and > 20 micrograms/dl in infected mice; and (c) decreases in thymic mass, > 30% in uninfected and up to 95% in infected mice. These changes are known to be associated with circulating TNF. Northern blot and in situ hybridization analyses demonstrated that IL-12 induced TNF-alpha expression and that LCMV infection synergized with IL-12 for induction of this factor. Antibodies neutralizing TNF reversed all of the IL-12-induced toxicities in LCMV-infected mice including the immunotoxicities against CD8+ T cells and anti-viral defenses. The TNF-mediated immunotoxicities appeared to result from an induced cellular sensitivity to the factor, as splenic leukocytes and CD8+ T cell subsets isolated from LCMV-infected mice were more sensitive to TNF-mediated cytotoxicity in culture than were equivalent populations prepared from uninfected mice. Experiments with the glucocorticoid type II receptor antagonist, RU486, demonstrated that endogenous glucocorticoids were secondary intermediaries in IL-12-induced thymic atrophy. Studies in IL-2-deficient mice showed that the synergism was dependent upon endogenous IL-2. The results delineate a unique mechanism of TNF-mediated toxicity. In addition, they have significant implications concerning potential detrimental consequences of in vivo TNF induction and of IL-12 administration for protective anti-viral responses.

Animals↗
PubMed1995

Differential activation of adrenal steroid receptors in neural and immune tissues of Sprague Dawley, Fischer 344, and Lewis rats.

Sprague Dawley (SD), Fischer 344 (F344), and Lewis (LEW) rats are used in a wide variety of laboratory studies. Compared to SD and LEW rats, F344 rats show significantly greater corticosterone secretion in response to stress, or to immune challenge. These strain differences in hypothalamic-pituitary-adrenal (HPA) axis responsivity have been the basis for many comparative studies investigating immunological and behavioural differences between the three strains. However, the effects of these strain differences in HPA axis responsivity have not been investigated at the level of adrenal steroid receptor activation in target tissues. The present study demonstrates that compared to SD and LEW rats, F344 rats exhibited a greater magnitude of Type II adrenal steroid receptor activation in brain tissues during stress. In contrast, Type II receptor activation in immune tissues of F344 rats following stress was similar to that of SD rats. Importantly, LEW rats exhibited the lowest magnitude of activation of Type II receptors in immune tissues during stress. No differences were observed between strains in the extent of stress-induced Type I adrenal steroid receptor activation. The observed differences between strains in corticosteroid-binding globulin (CBG) levels in plasma, pituitary, and immune tissue may mediate the differential access of corticosterone to neural versus immune tissues. These results indicate that strain differences in corticosterone secretion are manifested by differences in Type II receptor activation in neural as well as immune tissues. Moreover, they suggest that increased access of corticosterone to adrenal steroid receptors in brain areas of F344 rats may contribute to behavioural differences between strains, whereas decreased access of hormone to receptors in immune tissues of LEW rats may contribute to strain differences in susceptibility to autoimmune disease.

Adrenal Glands↗
PubMed1995

Natural killer cell activity in major depression: a prospective study of the in vivo effects of desmethylimipramine treatment.

To evaluate NK activity changes associated with both the diagnosis of major depressive disorder (MDD) and the in vivo treatment of MDD with the tricyclic antidepressant desmethylimipramine (DMI), 15 MDD outpatients (11 females, four males) and eight controls (six females, two males) were evaluated prospectively at intake and after an average of 12 weeks of standardized DMI treatment. Plasma DMI concentrations at follow-up and severity of depression using the Extracted Hamilton Depression Rating Scale (EH) score at both intake and follow-up were also evaluated. At intake, NK activity was significantly higher in depressed patients compared to controls (P < 0.0001) while at follow-up NK activity was not different between the two groups. NK activity decreased from intake to follow-up in depressed patients but not in controls. A second analysis of NK activity was performed by dividing depressed patients into responders and nonresponders (EH > or = 8 at follow-up). At intake, there was no difference between responders and nonresponders while at follow-up NK activity was lower in nonresponders (P < 0.0001). Only nonresponders had a significant decrease in NK activity from intake to follow-up. No correlation was found between DMI blood level and NK activity, and no difference in NK activity was present between those with the highest and lowest DMI blood levels. Although it is apparent that both MDD and its treatment influenced NK activity in this study, it is unclear whether the decrease in NK activity in nonresponding patients was a function of persistent depressed mood and/or DMI treatment.

Adult↗
PubMed1995

Glucocorticoid receptors in depression.

During major depression, dysfunction of limbic structures resulting in hypersecretion of corticotropin-releasing factor (CRF) is believed to cause the well-known hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in this disorder. Nonsuppression of the HPA axis by dexamethasone in depressed patients suggest that this increased CRF secretion may be due, at least in part, to altered feedback inhibition by glucocorticoids. Because glucocorticoid-induced feedback inhibition of the HPA axis is mediated by glucocorticoid receptors (GRs) in the brain and pituitary, the possibility that depression is associated with a primary alteration in GRs number and/or function has been an important consideration regarding the pathophysiology of the depressive disorders. Nevertheless, studies investigating GRs kinetics in depressed patients have been inconsistent. In some studies, decreased GRs number in depressed patients has been observed; others have obtained discordant results. The inconsistency of results may be due to a number of factors, including patient heterogeneity, the cell populations sampled, and the methods used to determine receptors number. Fewer studies have investigated the functional sensitivity of cells to the inhibitory effects of glucocorticoids, but they have been more consistent, showing increased resistance of cells from depressed patients to the inhibitory effects of glucocorticoids on immune function. In view of intriguing data indicating monoamine regulation of GR number and function in a hormone independent fashion along with the well-known effects of glucocorticoids on behavior, further scrutiny of the role of GR in depression and its treatment is warranted.

Antidepressive Agents↗