Non-genomic effects of glucocorticoids in the neural system: Evidence, mechanisms and implications

doi:10.1016/S0301-0082(01)00012-0

Progress in Neurobiology

Volume 65, Issue 4, November 2001, Pages 367-390

https://doi.org/10.1016/S0301-0082(01)00012-0 Get rights and content

Abstract

Complementing the classical concept of genomic steroid actions, here we (i) review evidence showing that important neural effects of glucocorticoids are exerted by non-genomic mechanisms; (ii) describe known mechanisms that may underlie such effects; (iii) summarize the functions and implications of non-genomic mechanisms and (iv) outline future directions of research. The role of non-genomic mechanisms is to shape the response of the organism to challenges that require a substantial reorganization of neural and somatic functions and involve massive behavioral shifts. Non-genomic effects may (i) prepare the cell for subsequent glucocorticoid-induced genomic changes, (ii) bridge the gap between the early need of change and the delay in the expression of genomic effects and (iii) may induce specific changes that in some instances are opposite to those induced by genomic mechanisms. The latter can be explained by the fact that challenging situations require different responses in early (acute) and later (chronic) phases. Data show that non-genomic mechanisms of glucocorticoid action play a role in both pathological phenomena and the expression of ameliorative pharmacological effects. Non-genomic mechanisms that underlie many glucocorticoid-induced neural changes constitute a for long overlooked controlling factor. Despite the multitude and the variety of accumulated data, important questions remain to be answered.

Introduction

There is growing evidence suggesting that neural and hormonal steroids use multiple transduction pathways, either genomic or non-genomic or both. In the case of glucocorticoids, genomic effects are well documented. Gene transcription is affected by these hormones in several steps as follows: (i) glucocorticoids bind to receptor complexes located in the cytoplasm; (ii) the glucocorticoid receptor complexes release associated (mainly heat-shock) proteins upon binding the ligand; (iii) the receptor–ligand complex translocates to the nucleus and binds to specific recognition sites; (iv) gene transcription is enhanced or inhibited depending on the type of the glucocorticoid receptor and the specific genomic site. Because of this mechanism, glucocorticoids induce long term changes in neural function (Joëls and de Kloet, 1994, Webster and Cidlowsky, 1999).

Glucocorticoids affect neural function also via rapidly developing mechanisms that do not involve a genomic component (Duval et al., 1983, Wehling, 1995, Wehling, 1997, Haller et al., 1998b, Borski, 2000, Falkenstein et al., 2000a, Falkenstein et al., 2000b). Non-genomic mechanisms appear to be activated by a series of other steroids as well (progesterone, estrogens, testosterone, aldosterone, vitamin D₃, and neurosteroids; McEwen, 1991, Wehling, 1995, Benten et al., 1997, Wehling, 1997, Baulieu, 1998). Evidence accumulated later suggests that non-genomic mechanisms activated by glucocorticoids involve various brain areas, neurotransmitter, and second messenger systems as well as behaviors (Table 1). The overview suggests that non-genomic effects of glucocorticoids are one of the major keys to understand the role of these hormones in controlling brain function. Nevertheless, non-genomic effects of glucocorticoids are still poorly understood. Moreover, discriminating between genomic and non-genomic mechanisms is difficult in some cases.

The aim of this review is to summarize data on the non-genomic effects of glucocorticoids in the neural system. After establishing criteria for differentiating genomic and non-genomic mechanisms, we will (i) summarize experimental evidence for the existence of non-genomic glucocorticoid effects in the neural system; (ii) describe known mechanisms that may underlie such effects; (iii) summarize the functions and implications of non-genomic mechanisms and (iv) outline future directions of research.

Section snippets

Criteria for differentiating genomic and non-genomic effects

The classical genomic mechanism of glucocorticoid action has several particularities that can be used as criteria for differentiating genomic and non-genomic mechanisms. In principle, glucocorticoid effects that are incompatible with the particularities of the genomic mechanism should be considered as being mediated by other (i.e. non-genomic) mechanisms.

Based on the particularities of the genomic mechanism, three criteria have been established for identifying non-genomic mechanisms of

Effects occurring within seconds

Locally applied glucocorticoids (corticosterone, cortisol and/or dexamethasone) rapidly affected spontaneous neuronal firing rate or multiunit activity in various brain regions (Ruf and Steiner, 1967, Michal, 1974, Avanzino et al., 1983, Avanzino et al., 1984, Avanzino et al., 1987a, Saphier and Feldman, 1988, Chen et al., 1991). Dosage is difficult to assess in iontophoretic or microelectrophoretic studies. However, the low currents applied (2–20 nA) suggests that low amounts of

Non-genomic mechanisms of rapid glucocorticoid effects

Neural and behavioral studies clearly show that non-genomic effects of glucocorticoids cannot be explained by one single mechanism. This assumption is supported by the following findings: (i) some rapid, non-genomic effects can be abolished by the blockade of the classical, generically linked GRs (Hua and Chen, 1989, Chen et al., 1991, Liu et al., 1995, Croxtall et al., 2000) while others do not depend on GRs (Venero and Borrell, 1999); (ii) in some instances, the artificial glucocorticoid

The specificity of the effect

Ligand specificity of non-genomic mechanisms activated by glucocorticoids has not always been a concern for those who studied rapid, non-genomic effects of glucocorticoids. When tested, however, glucocorticoid effects were not produced by a number of other steroids (see above). Noteworthy, glucocorticoid effects appear to be different from the effects of neurosteroids as well. As shown above, the effects of glucocorticoids on ligand binding to the GABA_A receptor was opposite to the change

Future directions of research

The existence of non-genomic glucocorticoid effects can be considered established, with several possible molecular mechanisms explaining such effects, and various functions controlled by such mechanisms. Thus, theoretical and practical implications of non-genomic glucocorticoid effects are of major importance, and yet, non-genomic effects of glucocorticoids and their implications are poorly understood.

Concluding remarks

The existence of non-genomic mechanisms that mediate part of the effects of glucocorticoids can be considered established. Several molecular mechanisms that can mediate such effects were reviewed in detail. The probable role of these mechanisms is to shape the response of the organism to challenges that require a substantial reorganization of neural and somatic functions and involve massive behavioral shifts. Non-genomic effects may (i) prepare the cell for subsequent glucocorticoid-induced

Acknowledgements

This work was supported by OTKA grant T 025844 and T 025845. We thank to Péter Csermely for his advices.

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Non-genomic effects of glucocorticoids in the neural system: Evidence, mechanisms and implications

Abstract

Introduction

Section snippets

Criteria for differentiating genomic and non-genomic effects

Effects occurring within seconds

Non-genomic mechanisms of rapid glucocorticoid effects

The specificity of the effect

Future directions of research

Concluding remarks

Acknowledgements

Eur. J. Pharmacol.

Neurosci. Lett.

Neurosci. Lett.

Neurosci. Lett.

Psychoneuroendocrinology

FEBS Lett.

J. Psychosom. Res.

Horm. Behav.

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J. Biol. Chem.

Horm. Behav.

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J. Steroid. Biochem. Mol. Biol.

Gen. Comp. Endocrinol.

Pharmacol. Biochem. Behav.

Brain Res.

Physiol. Behav.

Biochem. Pharmacol.

Physiol. Behav.

Biochim. Biophys. Acta

Pharmacol. Biochem. Behav.

Physiol. Behav.

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Neurosci. Biobehav. Rev.

Physiol. Behav.

Biochem. Biophys. Res. Commun.

Brain Res. Mol. Brain Res.

Biochem. Biophys. Res. Commun.

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Pharmacol. Biochem. Behav.

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Brain Res.

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Eur. J. Pharmacol.

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Arch. Gen. Psychiatry

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Am. J. Physiol.

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