Cited by 428Neuroscience and Neuropharmacology ResearchEstrogen and related hormone effectsStress Responses and Cortisol

Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties

Rupprecht, R.·2003·Psychoneuroendocrinology

Abstract

Steroids influence neuronal function through binding to cognate intracellular receptors which may act as transcription factors in the regulation of gene expression. In addition, certain so-called neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially distinct 3alpha-reduced metabolites of progesterone and deoxycorticosterone are potent positive allosteric modulators of gamma-aminobutyric acid type A (GABA(A)) receptors. However, also classical steroid hormones such as 17beta-estradiol, testosterone and progesterone are neuroactive steroids because they may act as functional antagonists at the 5-hydroxytryptamine type 3 (5-HT(3)) receptor, a ligand-gated ion channel or distinct glutamate receptors. A structure-activity relationship for the actions of a variety of steroids at the 5-HT(3) receptor was elaborated that differed considerably from that known for GABA(A) receptors. Although a bindings site for steroids at GABA(A) receptors is still a matter of debate, meanwhile there is also evidence that steroids interact allosterically with ligand-gated ion channels at the receptor membrane interface. On the other hand, also 3alpha-reduced neuroactive steroids may regulate gene expression via the progesterone receptor after intracellular oxidation into 5alpha-pregnane steroids. Animal studies showed that progesterone is converted rapidly into GABAergic neuroactive steroids in vivo. Progesterone reduces locomotor activity in a dose-dependent fashion in male Wistar rats. Moreover, progesterone and 3alpha-reduced neuroactive steroids produce a benzodiazepine-like sleep EEG profile in rats and humans. During major depression, there is a disequilibrium of such 3alpha-reduced neuroactive steroids which is corrected by successful treatment with antidepressant drugs. Neuroactive steroids may further be involved in the treatment of depression and anxiety with antidepressants in patients during ethanol withdrawal. Studies in patients with panic disorder suggest that neuroactive steroids may also play a role in modulating human anxiety. Both the genomic and non-genomic effects of steroids in the brain may contribute to the pathophysiology of psychiatric disorders and the mechanisms of action of antidepressants. Neuroactive steroids affect a broad spectrum of behavioral functions through their unique molecular properties and may represent a new treatment strategy for neuropsychiatric disorders.

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Crossref · 10.1016/s0306-4530(02)00064-1

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Authors
Rupprecht, R.
Affiliations
Max Planck Institute of Psychiatry (DE)
Corresponding author
Rupprecht, R.
Venue
Psychoneuroendocrinology
Publisher
Elsevier BV
Published
2003-02
Volume
28
Issue
2
Pages
139-168
ISSN
0306-4530 (ISSN-L)
OpenAlex
W2047844288
Cited by
427
References
151
Citations by year
2026: 4 · 2025: 5 · 2024: 12 · 2023: 14 · 2022: 13 · 2021: 6 · 2020: 11 · 2019: 14 · 2018: 13 · 2017: 6 · 2016: 13 · 2015: 18 · 2014: 14 · 2013: 18 · 2012: 26
FWCI
1.86
Type
journal article
Language
en
Open access
closed
Locations
  • Psychoneuroendocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • Max Planck Institute for Plasma Physics (submittedVersion)
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
neurosteroids, progesterone, deoxycorticosterone, GABA-A receptor modulation, 5-HT3 receptor antagonism, glutamate receptors, non-genomic steroid action, steroid hormone receptors, locomotor activity, sleep EEG, depression, anxiety, ethanol withdrawal, panic disorder, antidepressants, mental illness
MeSH terms
Anesthesia, Animals, Anticonvulsants, Antidepressive Agents, Humans, Nervous System, Receptors, GABA-A, Receptors, Serotonin, Sleep, Steroids, Antipsychotic Agents, Anti-Anxiety Agents, Gene Expression, Receptors, Neurotransmitter

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