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Divergent neuroactive steroid responses to stress and ethanol in rat and mouse strains: relevance for human studies

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Abstract

Rationale

Neuroactive steroids are endogenous or synthetic steroids that rapidly alter neuronal excitability via membrane receptors, primarily γ-aminobutyric acid type A (GABAA) receptors. Neuroactive steroids regulate many physiological processes including hypothalamic–pituitary–adrenal (HPA) axis function, ovarian cycle, pregnancy, aging, and reward. Moreover, alterations in neuroactive steroid synthesis are implicated in several neuropsychiatric disorders.

Objectives

This review will summarize the pharmacological properties and physiological regulation of neuroactive steroids, with a particular focus on divergent neuroactive steroid responses to stress and ethanol in rats, mice, and humans.

Results

GABAergic neuroactive steroids exert a homeostatic regulation of the HPA axis in rats and humans, whereby the increase in neuroactive steroid levels following acute stress counteracts HPA axis hyperactivity and restores homeostasis. In contrast, in C57BL/6J mice, acute stress decreases neurosteroidogenesis and neuroactive steroids exert paradoxical excitatory effects upon the HPA axis. Rats, mice, and humans also differ in the neuroactive steroid responses to ethanol. Genetic variation in neurosteroidogenesis may explain the different neuroactive steroid responses to stress or ethanol.

Conclusions

Rats and mouse strains show divergent effects of stress and ethanol on neuroactive steroids in both plasma and brain. The study of genetic variation in the various processes that determine neuroactive steroids levels as well as their effects on cell signaling may underlie these differences and may play a relevant role for the potential therapeutic benefits of neuroactive steroids.

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Acknowledgments

This work was supported by UO1-AA020935 to ALM, UO1-AA013641 to PP, and by the Bowles Center for Alcohol Studies. We acknowledge the myriad contributions of Robert H. Purdy to the field of neuroactive steroids in whose memory we dedicate this work.

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  1. Neuroscience Institute, National Research Council of Italy (CNR), Cittadella Universitaria, 09042, Monserrato, Cagliari, Italy

    Patrizia Porcu

  2. Departments of Psychiatry and Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    A. Leslie Morrow

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Correspondence to Patrizia Porcu.

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Porcu, P., Morrow, A.L. Divergent neuroactive steroid responses to stress and ethanol in rat and mouse strains: relevance for human studies. Psychopharmacology 231, 3257–3272 (2014). https://doi.org/10.1007/s00213-014-3564-8

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