Trends in Neurosciences
Volume 22, Issue 9, 1 September 1999, Pages 410-416
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Review
Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives

https://doi.org/10.1016/S0166-2236(99)01399-5Get rights and content

Abstract

Steroids influence neuronal function by binding to intracellular receptors that can act as transcription factors and regulate gene expression. In addition, some so-called ‘neuroactive steroids’ are potent modulators of an array of ligand-gated ion channels and of distinct G-protein coupled receptors via nongenomic mechanisms, and they can influence sleep and memory. This article describes how these neuroactive steroids modulate neurotransmitter receptors and addresses the neuropsychopharmacological potential that arises from the intracellular crosstalk between genomic and nongenomic steroid effects. Neuroactive steroids could also have a role in the response to stress and the treatment of psychiatric disorders, such as depression, and, as they affect a broad spectrum of behavioral functions through their unique molecular properties, they could constitute a yet unexploited class of drugs.

Section snippets

Sources and biosynthesis of neuroactive steroids

Owing to their lipophilic nature, steroids that are produced in various endocrine organs can easily cross the blood–brain barrier. However, a variety of neuroactive steroids can be synthesized in the brain itself without the aid of peripheral sources16. These steroids that are formed within the brain from cholesterol are often defined as ‘neurosteroids’16. Direct evidence for steroid synthesis within the brain has come from experiments that demonstrate the formation of steroids in rat glial

Steroid modulation of GABAA receptors

In 1986, it was shown for the first time that the neuroactive steroids 3α,5α-THP and 3α,5α-THDOC could modulate neuronal excitability via their interaction with GABAA receptors4. These receptors consist of various subunits that form ligand-gated ion channels with considerable homology to glycine, nicotinic acetylcholine and 5-HT3 receptors5, 6, 19. The steroids 3α,5α-THP and 3α,5α-THDOC were able not only to displace t-butylbicyclophosphorothionate (TBPS) from the Cl channel but also to

Pharmacological effects of neuroactive steroids

The actions of neuroactive steroids at the molecular level provide the basis for their modulation of a broad spectrum of physiological and pathological conditions (Box 1). For example, the NMDA-receptor antagonism produced by estrogens and 3α-reduced pregnane steroids might, in part, account for their neuroprotective properties26, 28. Moreover, in view of the reported memory-enhancing effects of pregnenolone41 and DHEA (Ref. 42) in animal studies, steroids that are negative allosteric

Outlook and perspectives

The term ‘neuroactive steroids’, which was initially adopted for steroids that modulate neuronal excitability via specific interactions with neurotransmitter receptors, has been challenged by the identification of steroid hormones that modulate various neurotransmitter receptors allosterically and by the genomic effects of neuroactive steroids that modulate the GABAA receptor. These observations underline the importance of the intracellular crosstalk between genomic and nongenomic steroid

Acknowledgements

We thank Christian Behl and Bettina Hermann for their critical reading of the manuscript. The work on neuroactive steroids at the Max Planck Institute of Psychiatry in Munich is supported by the Gerhard Heβ Programm of the Deutsche Forschungsgemeinschaft to R.R.

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