Realising the therapeutic potential of neuroactive steroid modulators of the GABAA receptor
Open accessAbstract
In the 1980s particular endogenous metabolites of progesterone and of deoxycorticosterone were revealed to be potent, efficacious, positive allosteric modulators (PAMs) of the GABAA receptor (GABAAR). These reports were followed by the discovery that such steroids may be synthesised not only in peripheral endocrine glands, but locally in the central nervous system (CNS), to potentially act as paracrine, or autocrine “neurosteroid” messengers, thereby fine tuning neuronal inhibition. These discoveries triggered enthusiasm to elucidate the physiological role of such neurosteroids and explore whether their levels may be perturbed in particular psychiatric and neurological disorders. In preclinical studies the GABAAR-active steroids were shown to exhibit anxiolytic, anticonvulsant, analgesic and sedative properties and at relatively high doses to induce a state of general anaesthesia. Collectively, these findings encouraged efforts to investigate the therapeutic potential of neurosteroids and related synthetic analogues. However, following over 30 years of investigation, realising their possible medical potential has proved challenging. The recent FDA approval for the natural neurosteroid allopregnanolone (brexanolone) to treat postpartum depression (PPD) should trigger renewed enthusiasm for neurosteroid research. Here we focus on the influence of neuroactive steroids on GABA-ergic signalling and on the challenges faced in developing such steroids as anaesthetics, sedatives, analgesics, anticonvulsants, antidepressants and as treatments for neurodegenerative disorders.
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GABAergic transmission is positively correlated with gonadal-hormone-derived neurosteroids, notably allopregnanolone.
“Thereafter, we showed that GABAergic transmission is positively correlated with gonadal-hormone-derived neurosteroids, notably allopregnanolone”
From Fibromyalgia pathogenesis explained by a neuroendocrine multistable model (2024) · cites this paper as [42]
The Introduction describes allopregnanolone, a progesterone metabolite, as a positive modulator of GABAA receptors. The “Neuroactive steroids and GABAAR subtypes” section says it enhances tonic inhibition and prolongs phasic inhibition. These passages support a positive effect on GABAergic transmission, but do not establish the claimed correlation between transmission and neurosteroid levels. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAllopregnanolone and other neurosteroids act on both synaptic (gamma-type) and extrasynaptic (delta-type) GABAA receptors, prolonging phasic and enhancing tonic GABAergic inhibition, respectively.
“Allopregnanolone and other neurosteroids act on both synaptic (γ-type) and extrasynaptic (δ-type) GABAA receptors, thereby prolonging phasic and enhancing tonic GABAergic inhibition, respectively [42].”
From Fibromyalgia pathogenesis explained by a neuroendocrine multistable model (2024) · cites this paper as [42]
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- Authors
- Belelli, D., Hogenkamp, D., Gee, K. W., & Lambert, J. J.
- Affiliations
- University of Dundee (GB)
- University of California, Irvine (US)
- Corresponding author
- Lambert, Jeremy J.
- Venue
- Neurobiology of Stress
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 12
- Pages
- 100207
- ISSN
- 2352-2895 (ISSN-L)
- PMC
- PMC7231973
- OpenAlex
- W2997573921
- Cited by
- 67
- References
- 152
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 9 · 2023: 6 · 2022: 14 · 2021: 15 · 2020: 8 · 2019: 1
- FWCI
- 4.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neurobiology of Stress (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Keywords
- neurosteroids, GABAA receptor, positive allosteric modulators, allopregnanolone, brexanolone, progesterone metabolites, GABAergic neurotransmission, anesthesia, sedation, analgesia, antiepileptic drugs, antidepressants, neurodegenerative diseases, postpartum depression, drug development
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