Cited by 130Stress Responses and CortisolNeuroscience and Neuropharmacology ResearchPosttraumatic Stress Disorder Research

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The Role of HPA Axis and Allopregnanolone on the Neurobiology of Major Depressive Disorders and PTSD

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Almeida, Felipe Borges, Pinna, Graziano, Barros, Helena Maria Tannhauser·2021·International Journal of Molecular Sciences

DOI 10.3390/ijms22115495PMC PMC8197074

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Abstract

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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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
ORCID: Almeida, Felipe Borges
Pinna, Graziano
Barros, Helena Maria Tannhauser
Venue: International Journal of Molecular Sciences
Publisher: MDPI AG
Published: 2021-05-23
Volume: 22
Issue: 11
Pages: 5495
ISSN: 1422-0067 (ISSN-L)
DOI: 10.3390/ijms22115495
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: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
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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The Role of HPA Axis and Allopregnanolone on the Neurobiology of Major Depressive Disorders and PTSD

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