Characterization and functional significance of glucocorticoid receptors in patients with major depression: modulation by antidepressant treatment

Calfa, Gastón; Kademian, Silvia; Ceschin, Danilo Guillermo; Vega, Gloria Lena; Rabinovich, Gabriel A.; Volosin, Márta

doi:10.1016/s0306-4530(02)00051-3

Cited by 82 publications

(36 citation statements)

References 39 publications

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“…These observations have led to the idea that a primary component in the development of depression may involve factors which influence negative feedback inhibition of the HPA axis, such as forebrain GR. This is supported by studies finding decreased GR mRNA expression in the prefrontal cortex of patients with depression as well as in postmortem tissue from suicide victims (4,6,27). Here we demonstrate that a primary deficiency of forebrain GR leads to increased nadir and peak circadian corticosterone release and impaired negative feedback inhibition of the HPA axis, paralleling what is seen in glucocorticoid feedback-resistant human depressive patients.…”

Section: Forebrain Gr Provides Negative Feedback Inhibition To the Hpmentioning

confidence: 58%

“…Various observations suggest that these changes may be central to the pathogenesis of depression. Impairments in negative feedback inhibition are believed to be diagnostic of depression, with between 40 and 80% of patients with MDD showing impaired glucocorticoid suppression in the DST (4,22). Normalization of these HPA abnormalities is associated with successful antidepressant treatment (23,24).…”

Section: Forebrain Gr Provides Negative Feedback Inhibition To the Hpmentioning

confidence: 99%

“…Research both in humans and in animal models have implicated forebrain glucocorticoid receptors (GRs) in HPA axis regulation and depression (4,5). Studies examining postmortem tissue from suicide victims and individuals with major depressive disorder (MDD) have revealed decreased GR mRNA expression in the hippocampus and cortex (6).…”

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confidence: 99%

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Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior

Boyle

Brewer

Funatsu

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

335

254

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Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark of major depressive disorder. A number of studies have shown that this dysregulation is correlated with impaired forebrain glucocorticoid receptor (GR) function. To determine whether a primary, acquired deficit in forebrain GR signaling is an etiologic factor in the pathogenesis of depression, we generated a line of mice with time-dependent, forebrain-specific disruption of GR (FBGRKO). These mice develop a number of both physiological and behavioral abnormalities that mimic major depressive disorder in humans, including hyperactivity of the HPA axis, impaired negative feedback regulation of the HPA axis and, increased depression-like behavior. Importantly, a number of these abnormalities are normalized by chronic treatment with the tricyclic antidepressant, imipramine. Our findings suggest that imipramine's proposed activities on forebrain GR function are not essential for its antidepressant effects, and that alteration in GR expression may play a causative role in disease onset of major depressive disorder. knockout mice M ajor depression is a serious neuropsychiatric illness that the World Health Organization predicts will soon be the world's greatest public health burden (www.nimh.nih.gov͞publicat͞ burden). Although both genetic and environmental factors are known to contribute to its pathogenesis, two fundamental questions remain unanswered. First, what are the primary genetic factors that contribute to a predisposition for depression? Second, what interacting biochemical pathways lead to the disease state? There are a number of lines of evidence that suggest that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may be a primary factor in the pathogenesis of depression (1). Depressed patients show hyperactivity of the HPA axis that may result from impairments in negative feedback regulation of glucocorticoid release (2). Moreover, normalization of these HPA axis abnormalities is associated with successful antidepressant treatment, and patients whose HPA abnormalities do not normalize are significantly more likely to relapse (3).Research both in humans and in animal models have implicated forebrain glucocorticoid receptors (GRs) in HPA axis regulation and depression (4, 5). Studies examining postmortem tissue from suicide victims and individuals with major depressive disorder (MDD) have revealed decreased GR mRNA expression in the hippocampus and cortex (6). Importantly, GR mRNA expression and hormone-binding activity are both increased after antidepressant treatment (7). In addition, a number of animal models of depression have been shown to be associated with decreased forebrain GR expression. In rodents, exposure to early life maternal neglect, which, in humans, is known to increase the risk of depression, leads to a depression like-phenotype (8) that is associated with decreased hippocampal GR expression (9). Conversely, an early nurturing environment led to increased hippocampal GR expression and decreased suscept...

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Section: Forebrain Gr Provides Negative Feedback Inhibition To the Hpmentioning

confidence: 58%

Section: Forebrain Gr Provides Negative Feedback Inhibition To the Hpmentioning

confidence: 99%

See 1 more Smart Citation

Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior

Boyle

Brewer

Funatsu

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

335

254

View full text Add to dashboard Cite

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“…Other studies that assessed GR function or GR binding characteristics also included patients with comorbid MDD; therefore, it is not likely that inclusion of patients with comorbid MDD can account for the observed differences between our data and previous studies. As several studies have reported a decreased effect of DEX on T-cell proliferation in MDD 56,57 it is important to investigate the effect of a comorbid MDD. However, our additional analyses suggest that a comorbid MDD did not cause the observed differences.…”

Section: Discussionmentioning

confidence: 99%

Leukocyte glucocorticoid receptor expression and immunoregulation in veterans with and without post-traumatic stress disorder

et al. 2007

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Post-traumatic stress disorder (PTSD) is associated with a dysregulation of the hypothalamus-pituitary-adrenal axis (HPA axis). In addition, there is evidence for altered glucocorticoid receptor (GR) expression and function in peripheral blood mononuclear cells. The aim of the present study was to differentiate between the effect of trauma exposure and PTSD on leukocyte GR expression and glucocorticoid immune regulation. Leukocyte GR binding characteristics and glucocorticoid sensitivity of immune activity, determined as the effect of dexamethasone (DEX) on in vitro cytokine release and T-cell proliferation, were compared between veterans with PTSD, traumatized veterans without PTSD and healthy controls. Leukocyte GR density was significantly lower in veterans with and without PTSD compared to healthy controls. DEX-induced inhibition of T-cell proliferation was significantly lower in PTSD compared to trauma and healthy controls. DEX-induced increase in lipopolysaccharidestimulated interleukin-10 was less pronounced in traumatized veterans with and without PTSD compared to healthy controls. No group differences were observed in the effect of DEX on other cytokines or in baseline immune activity, except for lower tumor necrosis factor-a production in PTSD patients compared to healthy controls. The results suggest that trauma exposure is sufficient to induce changes in GR binding characteristics, whereas resistance of T-cell proliferation to DEX only occurs in PTSD. DEX resistance of in vitro immune activity was not a general phenomenon, but was restricted to specific immune functions.

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“…Since hypothalamic glucocorticoid receptors' (GR) sensitivity to cortisone decreases, no negative feedback effect arises, this results in increased hypothalamic CRH release (47). The reduced number of GR in mononuclear cells in depressed patients and its restitution by treatment also supports the presence of GR resistance (48). A nonsuppression may occur in GAD due to similar mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of hypothalamo-pituitary-adrenal axis activity by using dexamethasone suppression test in patients with panic disorder and generalized anxiety disorder

Hacımusalar¹,

Eşel²

2017

Dusunen Adam

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Evaluation of hypothalamo-pituitary-adrenal axis activity by using dexamethasone suppression test in patients with panic disorder and generalized anxiety disorderObjective: The aim of this study was to investigate the role of hypothalamo-pituitary-adrenal (HPA) axis activity on the pathophysiology of anxiety disorders by examining the HPA axis activity in patients with panic disorder (PD) and generalized anxiety disorder (GAD).Method: Baseline and post dexamethasone suppression test (DST) serum concentrations of cortisol and dehydroepiandrosterone-sulfate (DHEA-S) were measured in patients with PD (n=24), GAD (n=21) and in healthy controls (n=20). Results:The baseline cortisol levels in GAD group were found lower than those of the patients with PD and healthy controls. Cortisol suppression by dexamethasone in GAD group was found to be lower than PD patients and healthy controls. Baseline and post-DST DHEA-S levels in the patients with PD and GAD were similar to those of the healthy controls. Yöntem: PB (n=24) ve YAB (n=21) olan hastalarda ve sağlıklı kontrollerde (n=20) bazal ve deksametazon baskılama testi (DST) uygulaması sonrasında kortizol ve dehidroepiandrosteron-sülfat (DHEA-S) değerleri ölçüldü.Bulgular: YAB grubunun bazal kortizol düzeyleri kontrol ve PB grubuna göre düşük bulundu. Ayrıca YAB grubunda deksametazonun kortizolu baskılaması kontrol ve PB grubuna göre düşük bulundu. PB ve YAB hastalarında bazal ve DST sonu DHEA-S düzeyleri kontrol grubuna benzer bulundu.Sonuç: YAB hastalarında bazal kortizol düzeyinin düşük olması ve DST'de kortizol baskılanmasının yetersiz oluşu bu hastalarda hem kortikotropin salgılatıcı hormon reseptörlerinde, hem de glukokortikoid reseptörlerinde bir aşağı ayarlama (down-regulation) olduğunu akla getirmektedir.Anahtar kelimeler: Dehidroepiandrosteron, deksametazon, yaygın anksiyete bozukluğu, panik bozukluğu

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Characterization and functional significance of glucocorticoid receptors in patients with major depression: modulation by antidepressant treatment

Cited by 82 publications

References 39 publications

Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior

Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior

Leukocyte glucocorticoid receptor expression and immunoregulation in veterans with and without post-traumatic stress disorder

Evaluation of hypothalamo-pituitary-adrenal axis activity by using dexamethasone suppression test in patients with panic disorder and generalized anxiety disorder

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