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The Role of HPA Axis and Allopregnanolone on the Neurobiology of Major Depressive Disorders and PTSD
Open accessAbstract
Under stressful conditions, the hypothalamic-pituitary-adrenal (HPA) axis acts to promote transitory physiological adaptations that are often resolved after the stressful stimulus is no longer present. In addition to corticosteroids (e.g., cortisol), the neurosteroid allopregnanolone (3α,5α-tetrahydroprogesterone, 3α-hydroxy-5α-pregnan-20-one) participates in negative feedback mechanisms that restore homeostasis. Chronic, repeated exposure to stress impairs the responsivity of the HPA axis and dampens allopregnanolone levels, participating in the etiopathology of psychiatric disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). MDD and PTSD patients present abnormalities in the HPA axis regulation, such as altered cortisol levels or failure to suppress cortisol release in the dexamethasone suppression test. Herein, we review the neurophysiological role of allopregnanolone both as a potent and positive GABAergic neuromodulator but also in its capacity of inhibiting the HPA axis. The allopregnanolone function in the mechanisms that recapitulate stress-induced pathophysiology, including MDD and PTSD, and its potential as both a treatment target and as a biomarker for these disorders is discussed.
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“Allopregnanolone has induced the GABAergic inhibition of HPA axis activation in female rats [93,94] and pregnant women [95].”
From Fibromyalgia pathogenesis explained by a neuroendocrine multistable model (2024) · cites this paper as [94]
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Metadata
- Authors
- Almeida, F. B., Pinna, G., & Barros, H. M. T.
- Affiliations
- Universidade Federal de Ciências da Saúde de Porto Alegre (BR)
- University of Illinois Chicago (US)
- Corresponding author
- Pinna, Graziano
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2021-05-23
- Volume
- 22
- Issue
- 11
- Pages
- 5495
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC8197074
- OpenAlex
- W3164510424
- Cited by
- 130
- References
- 84
- Citations by year
- 2026: 17 · 2025: 39 · 2024: 30 · 2023: 26 · 2022: 16 · 2021: 2
- FWCI
- 2.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior ((Code 001))
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (19/2551, Code 001)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Keywords
- hypothalamic-pituitary-adrenal axis, allopregnanolone, major depressive disorder, post-traumatic stress disorder, neurosteroids, GABAergic modulation, chronic stress, cortisol, dexamethasone suppression test, biomarkers, treatment goals
- MeSH terms
- Adaptation, Physiological, Animals, Antidepressive Agents, Chronic Disease, Corticosterone, Depressive Disorder, Major, Major Depressive Disorder, Female, gamma-Aminobutyric Acid, Humans, Hypothalamo-Hypophyseal System, Male, Models, Biological, Pituitary-Adrenal System, Pregnanolone, Receptors, GABA-A, Sex Characteristics, Stress, Physiological, Stress Disorders, Post-Traumatic, Stress, Psychological, Feedback, Physiological, GABA-A Receptor Agonists
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