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Neurosteroid, GABAergic and hypothalamic pituitary adrenal (HPA) axis regulation: what is the current state of knowledge in humans?

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Abstract

Rationale

A robust epidemiological literature suggests an association between chronic stress and the development of affective disorders. However, the precise biological underpinnings of this relationship remain elusive. Central to the human response and adaptation to stress, activation and inhibition of the hypothalamic pituitary adrenal (HPA) axis involves a multi-level, multi-system, neurobiological stress response which is as comprehensive in its complexity as it is precarious. Dysregulation in this complex system has implications for human stress related illness.

Objectives

The pioneering research of Robert Purdy and colleagues has laid the groundwork for advancing our understanding of HPA axis regulation by stress-derived steroid hormones and their neuroactive metabolites (termed neurosteroids), which are potent allosteric modulators of GABAA receptor function in the central nervous system. This review will describe what is known about neurosteroid modulation of the HPA axis in response to both acute and chronic stress, particularly with respect to the current state of our knowledge of this process in humans.

Results

Implications of this research to the development of human stress-related illness are discussed in the context of two human stress-related psychiatric disorders — major depressive disorder and premenstrual dysphoric disorder.

Conclusions

Neurosteroid-mediated HPA axis dysregulation is a potential pathophysiologic mechanism which may cross traditional psychiatric diagnostic classifications. Future research directions are identified.

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Acknowledgments

This research was supported by NIH R01-MH081837 and T32-MH093315.

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The authors declare that they have no conflicts of interest.

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  1. Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7175, USA

    Shannon K. Crowley & Susan S. Girdler

  2. Department of Psychiatry, CB#7175, UNC School of Medicine, University of North Carolina, Psychiatry Wing C, Chapel Hill, NC, 27599-7175, USA

    Susan S. Girdler

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Crowley, S.K., Girdler, S.S. Neurosteroid, GABAergic and hypothalamic pituitary adrenal (HPA) axis regulation: what is the current state of knowledge in humans?. Psychopharmacology 231, 3619–3634 (2014). https://doi.org/10.1007/s00213-014-3572-8

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