Adrenal steroid receptor activation in rat brain and pituitary following dexamethasone: Implications for the dexamethasone suppression test

Miller, Andrew H.; Spencer, Robert L.; Pulera, Mark; Kang, Sung Ha; McEwen, Bruce S.; Stein, Mary Kay

doi:10.1016/0006-3223(92)90175-y

Cited by 133 publications

(76 citation statements)

References 57 publications

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“…This consequently results in decreased expression of Fkbp5. In contrast, with the high dose of dexamethasone (300 μg/Kg), which potentially penetrates the blood-brain barrier (Miller et al, 1992), the brain may be flooded with this agonist, thereby mimicking a strong stress response. This is also in line with the induction of Fkbp5 expression in several brain regions.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Sawamura

Klengel

Armario

et al. 2015

Neuropsychopharmacol

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Posttraumatic stress disorder (PTSD) is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symptom relapse. In the present study, we used a putative animal model of PTSD that included presentation of immobilization stress (IMO) followed by fear conditioning (FC) a week later. We then investigated the acute effects of GR receptor activation on the extinction (EXT) of conditioned freezing, using dexamethasone administered systemically which is known to result in suppression of the HPA axis. In our previous work, IMO followed by tone-shockmediated FC was associated with impaired fear EXT. In this study, we administered dexamethasone 4 h before EXT training and then examined EXT retention (RET) 24 h later to determine whether dexamethasone suppression rescued EXT deficits. Dexamethasone treatment produced dose-dependent enhancement of both EXT and RET. Dexamethasone was also associated with reduced amygdala Fkbp5 mRNA expression following EXT and after RET. Moreover, DNA methylation of the Fkbp5 gene occurred in a dose-dependent and time course-dependent manner within the amygdala. Additionally, we found dynamic changes in epigenetic regulation, including Dnmt and Tet gene pathways, as a function of both fear EXT and dexamethasone suppression of the HPA axis. Together, these data suggest that dexamethasone may serve to enhance EXT by altering Fkbp5-mediated glucocorticoid sensitivity via epigenetic regulation of Fkbp5 expression.

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Section: Discussionmentioning

confidence: 99%

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Sawamura

Klengel

Armario

et al. 2015

Neuropsychopharmacol

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“…GR binding was determined using a previously described in vitro cytosolic exchange assay (Miller et al 1992). Cells were fractionated using a freeze/thaw procedure in a volume of 0.7 ml of binding buffer (10 mM Tris, 1 mM EDTA, 20 mM molybdic acid, 5 mM dithiothreitol, and 10% glycerol in double-distilled water, pH 7.4 at 4 Њ ), yielding an approximate final protein concentration of 0.5-2.5 mg/ml of cytosol.…”

Section: Gr Binding Assaymentioning

confidence: 99%

“…Specific GR binding was expressed as fmol/mg cytosolic protein. Protein content for all samples was determined according to the method of Bradford with use of BSA as a standard as described previously (Miller et al 1992). …”

Section: Gr Binding Assaymentioning

confidence: 99%

The Phosphodiesterase Type 4 Inhibitor, Rolipram, Enhances Glucocorticoid Receptor Function

Miller

Vogt

Pearce

2002

Neuropsychopharmacology

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Previous studies have demonstrated that antidepressants can enhance glucocorticoid receptor (GR) translocation and function, possibly through activation of cAMP and downstream cAMP dependent protein kinases. Accordingly, we examined GR function in cells treated with rolipram, a phosphodiesterase (PDE) type 4 inhibitor that antagonizes cAMP breakdown. Compared with vehicle-treated cells, rolipram alone and in combination with dexamethasone significantly enhanced GR function as measured in both mouseHyperactivity of the hypothalamic-pituitary adrenal (HPA) axis is a common and reproducible finding in patients with major depression (Pariante and Miller 2001;Holsboer 2000). A major factor responsible for these HPA axis changes is believed to be increased corticotropin releasing hormone (CRH), which may also contribute to the behavioral features of this disorder (Owens and Nemeroff 1993). Altered feedback regulation of CRH by glucocorticoids is one mechanism that may contribute to the CRH changes found in major depression (Pariante and Miller 2001;Holsboer 2000). Specifically, evidence exists that the receptors for glucocorticoids may become impaired in major depression, leading to glucocorticoid resistance in selected body tissues including the brain and immune system (Pariante and Miller 2001;Holsboer 2000). Recent evidence suggests that antidepressants may reverse glucocorticoid receptor changes in depression by direct effects on the glucocorticoid receptor (GR) (Pariante and Miller 2001;Holsboer 2000;Holsboer and Barden 1996). Both in vitro and in vivo data indicate that antidepressants can increase GR number and facilitate GR function (Pariante and Miller 2001;Holsboer and Barden 1996). Given evidence that a number of antidepressants have effects on signal transduction pathways involving cyclic AMP NO . 6 (cAMP) (Chen and Rasenick 1995a,b;Nestler et al. 1989;Nibuya et al. 1996), there has been speculation that the influence of antidepressants on GR is through their effects on cAMP-related signal transduction events (Pariante and Miller 2001).A large body of data demonstrates that cAMP signal transduction pathways are involved in the regulation of the GR. For example, direct evidence of facilitation of GR function has been demonstrated for ␤ 2 receptor agonists, cAMP, and protein kinase A (PKA) (Eickelberg et al. 1999;Schmidt et al. 2001;Sato et al. 1996;Rangarajan et al. 1992). Phosphodiesterases (PDE) are a group of enzymes that catalyze the breakdown of cyclic nucleotides (Beavo et al. 1994). The PDE isozyme type 4 is specific for cAMP and is expressed throughout the brain and immune system (Perez-Torres et al. 2000;Engels et al. 1994). Thus, inhibitors of PDE type 4 provide a pharmacologic strategy to increase prevailing cAMP levels in relevant target tissues.One PDE type 4 inhibitor, rolipram, has been shown to have antidepressant effects (Zhu et al. 2001;Bobon et al. 1988, Eckmann et al. 1988. Rolipram was first demonstrated to have potent antidepressant activity in animal models (Zhu et al. 2001;Wachte...

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“…Disregulation of the HPA axis associated with major depression is revealed by the dexamethasone suppression test (DST) (19,20). Although the DST is most likely working at the pituitary level (99), the underlying disregulation is undoubtedly of CNS origin and reflects increased drive upon the CRH and AVP systems of the hypothalamus (45) and constitutes a form of endogenously driven stress. A lessening of the adrenal steroid feedback effects on the hippocampus might be a contributing factor to elevated HPA activity in depression, and recent studies of Barden and co-workers with a transgenic mouse strain (7,56) have suggested that decreased forebrain Type II receptor expression might be a contributing factor to depression and a potential target of antidepressant therapy (56,102).…”

Section: The Hippocampus and Hpa Regulationmentioning

confidence: 99%

Stress and the Aging Hippocampus

McEwen

1999

Frontiers in Neuroendocrinology

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208

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The ''glucocorticoid cascade hypothesis'' of hippocampal aging has stimulated a great deal of research into the neuroendocrine aspects of aging and the role of glucocorticoids, in particular. Besides strengthening the methods for investigating the aging brain, this research has revealed that the interactions between glucocorticoids and hippocampal neurons are far more complicated than originally envisioned and involve the participation of neurotransmitter systems, particularly the excitatory amino acids, as well as calcium ions and neurotrophins. New information has provided insights into the role of early experience in determining individual differences in brain and body aging by setting the reactivity of the hypothalamopituitary-adrenal axis and the autonomic nervous system. As a result of this research and advances in neuroscience and the study of aging, we now have a far more sophisticated view of the interactions among genes, early development, and environmental influences, as well as a greater appreciation of events at the cellular and molecular levels which protect neurons, and a greater appreciation of pathways of neuronal damage and destruction. While documenting the ultimate vulnerability of the brain to stressful challenges and to the aging process, the net result of this research has highlighted the resilience of the brain and offered new hope for treatment strategies for promoting the health of the aging brain. KEY WORDS: stress; hippocampal aging; glucocorticoid cascade hypothesis. 1999 Academic Press INTRODUCTIONThe hippocampus is a particularly vulnerable and sensitive region of the brain that is also very important for declarative and spatial learning and memory (36). Hippocampal neurons are vulnerable to seizures, strokes, and head trauma, as well as responding to stressful experiences (27,92,130). At the same time they show remarkable plasticity, involving long-term synaptic potentiation and depression, dendritic remodeling, synaptic turnover, and neurogenesis in the case of the dentate gyrus (Fig 1) (17,27,92).The work of aus der Muhlen and Ockenfels (3) first drew attention to potentially toxic actions of adrenal steroids. The reported darkly stained neurons in the hippocampus of guinea pigs exposed to high levels of glucocorticoids, an observation that has been confirmed and extended to repeated stress in subsequent studies (41,100), although there are still some doubts as to whether ''dark neurons'' may be artifacts of tissue trauma (18). In 1968, we discovered receptors for adrenal steroids in hippocampus (95), and it is now known that two types of adrenal steroid receptors exist in the hippocampus and other brain regions and mediate a variety of adrenal steroid effects on excitability, neurochemistry, and structure (27). Landfield (68) and then Sapolsky (127,128) provided evidence for a role of adrenal steroids in neuronal aging in the hippocampus, leading to the formulation of the ''glucocorticoid cascade hypothesis '' (130). This hypothesis states that glucocorticoids participate in a ...

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Adrenal steroid receptor activation in rat brain and pituitary following dexamethasone: Implications for the dexamethasone suppression test

Cited by 133 publications

References 57 publications

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

The Phosphodiesterase Type 4 Inhibitor, Rolipram, Enhances Glucocorticoid Receptor Function

Stress and the Aging Hippocampus

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