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Neurosteroids: endogenous regulators of the GABAA receptor

Nature Reviews Neuroscience volume 6, pages 565–575 (2005)Cite this article

Key Points

  • Certain steroid metabolites of progesterone and deoxycorticosterone potently and specifically bind to the GABAA (γ-aminobutyric acid type A) receptor — the main inhibitory receptor in the mammalian CNS — to enhance receptor function. Consequently, these steroids have anxiolytic, analgesic, anticonvulsant, sedative, hypnotic and anaesthetic effects.

  • Such steroids are synthesized both in the periphery and in the CNS (neurosteroids), and, therefore, can act as both endocrine and paracrine messengers to facilitate inhibitory neurotransmission. The enzymes that synthesize and metabolize neurosteroids present new therapeutic targets.

  • Perturbations of neurosteroid levels are associated with various physiological (for example, stress, pregnancy and ageing), psychological (including depression, post-partum depression and premenstrual tension) and neurological (such as catamenial epilepsy) conditions.

  • Neurosteroid levels are altered by psychoactive drugs, such as ethanol, γ-hydroxybutyrate (GHB) and certain antidepressants, including fluoxetine; these effects might contribute to the behavioural actions of these drugs.

  • GABA is an inhibitory neurotransmitter, but it is also an important neurotrophic factor. Consequently, an unappreciated role for neurosteroids in brain development and plasticity is emerging. Furthermore, certain neurodegenerative diseases are associated with abnormal neurosteroid levels.

  • Given the ubiquitous expression of GABAA receptors throughout the CNS, physiological, pathophysiological or pharmacological changes in neurosteroid levels should nonselectively influence neuronal inhibition. However, the interactions between GABAA receptors and neurosteroids are highly selective, and discriminate not only between different neurons but also among different receptor pools in a neuron. This heterogeneity depends on receptor subunit composition, phosphorylation and local steroid metabolism.

Abstract

GABAA (γ-aminobutyric acid type A) receptors mediate most of the 'fast' synaptic inhibition in the mammalian brain and are targeted by many clinically important drugs. Certain naturally occurring pregnane steroids can potently and specifically enhance GABAA receptor function in a nongenomic (direct) manner, and consequently have anxiolytic, analgesic, anticonvulsant, sedative, hypnotic and anaesthetic properties. These steroids not only act as remote endocrine messengers, but also can be synthesized in the brain, where they modify neuronal activity locally by modulating GABAA receptor function. Such 'neurosteroids' can influence mood and behaviour in various physiological and pathophysiological situations, and might contribute to the behavioural effects of psychoactive drugs.

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Figure 1: Structure and synthesis of neurosteroids.
Figure 2: Neurosteroid modulation of recombinant and synaptic GABAA receptors.
Figure 3: Neurosteroids: local modulators of inhibitory neurotransmission.

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Acknowledgements

Some of the work reported here was supported by the Medical Research Council (MRC) and by the Commission of the European Communities Research and Technical Development (RTD) programme entitled 'Quality of Life and Management of Living Resources'. The authors would like to thank J. Peters for helpful discussions.

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Authors and Affiliations

  1. Division of Pathology and Neuroscience, Neurosciences Institute, Ninewells Hospital and Medical School, Dundee University, Dundee, DD19SY, UK

    Delia Belelli & Jeremy J. Lambert

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  1. Delia Belelli
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Correspondence to Jeremy J. Lambert.

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DATABASES

Entrez Gene

NPC1

Pkcε

VDAC1

VDAC2

OMIM

Alzheimer disease

Niemann-Pick disease type C

Parkinson disease

FURTHER INFORMATION

Belelli and Lambert's homepages

Glossary

PREGNANE STEROID

A saturated steroid nucleus that contains methyl groups at C18 and C19, and an ethyl side chain at C17.

5α-PREGNAN-3α-OL-20-ONE

A naturally occurring metabolite of progesterone that is synthesized in both the periphery and the CNS. This steroid potently and selectively enhances the function of the GABAA receptor.

GABA-MODULATORY

A term that is used to describe the actions of a drug that has little effect alone but, at relatively low concentrations, enhances the response that is mediated by GABA. Examples include diazepam, certain neuroactive steroids and many intravenous general anaesthetics, including etomidate, propofol and thiopental.

GABA-MIMETIC

A term that is used to describe the direct activation of the GABAA receptor by a drug. Examples include certain neuroactive steroids, etomidate, propofol and thiopental. The GABA-mimetic effect of these agents usually occurs at concentrations that are greater than those required for their GABA-modulatory effects.

NEUROSTEROID

A steroid that is synthesized in the nervous system.

CATAMENIAL EPILEPSY

In women with this type of epilepsy, seizures do not occur randomly but cluster in association with the menstrual cycle.

WHOLE-CELL-CLAMP TECHNIQUE

A high-resolution electrophysiological recording method that allows the electrical currents that flow across the cell membrane to be recorded under voltage-clamp conditions.

MINIATURE INHIBITORY POSTSYNAPTIC CURRENT

(mIPSC). The postsynaptic current that results from the activation of synaptic receptors by neurotransmitters (GABA or glycine) that are usually released from a single vesicle.

PHASIC INHIBITORY RESPONSE

The transient inhibitory response that results from the activation of postsynaptic GABAA receptors by the relatively high concentration of GABA that occurs in the synapse subsequent to vesicular release.

TONIC INHIBITION

An inhibitory response that is mediated by the activation of extra- or perisynaptic GABAA receptors through ambient concentrations of GABA. In some neurons, these receptors have a distinct subunit composition and, as a consequence, have a relatively high affinity for GABA and show little or no desensitization.

BENZODIAZEPINES

A chemical class of compounds that bind between the interfaces of the α- and γ-GABAA receptor subunits. Benzodiazepine 'agonists', such as diazepam, enhance GABA-evoked responses and, consequently, are sedative, anxiolytic and anticonvulsant. Benzodiazepine 'inverse agonists' decrease GABA-evoked responses, and are proconvulsant and anxiogenic. Benzodiazepine antagonists, such as flumazenil, prevent the actions of both benzodiazepine agonists and inverse agonists.

CORTICAL MICROSACS

A preparation of synaptosomes ('pinched off' nerve terminals) from cortical neurons.

ENANTIOMERS

A pair of stereoisomers that are nonsuperimposable mirror images of one another.

NEUROACTIVE STEROIDS

This term describes both synthetic and naturally occurring steroids that have an effect on neural function.

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Belelli, D., Lambert, J. Neurosteroids: endogenous regulators of the GABAA receptor. Nat Rev Neurosci 6, 565–575 (2005). https://doi.org/10.1038/nrn1703

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