The immediate and maintained effects of neurosteroids on GABAA receptors

D. Belelli; J. A. Peters; G. D. Phillips; J. J. Lambert

doi:10.1016/j.coemr.2022.100333

The immediate and maintained effects of neurosteroids on GABA_A receptors

D. Belelli, J. A. Peters, G. D. Phillips, J. J. Lambert (Lead / Corresponding author)

Research output: Contribution to journal › Review article › peer-review

7 Citations (Scopus)

123 Downloads (Pure)

Abstract

Allopregnanolone is an endogenous neurosteroid that acts in a rapid non-genomic manner to enhance the function of the GABA_A receptor (GABA_AR), the major inhibitory receptor in the mammalian central nervous system (CNS). Consequently, allopregnanolone elicits anxiolytic, antidepressant, anticonvulsant, analgesic and sedative effects. Endogenous allopregnanolone influences neural inhibition and behaviour, with perturbed neurosteroid levels implicated in depressive disorders. The approval of brexanolone (an allopregnanolone formulation) to treat postpartum depression (PPD) has encouraged optimism that they may provide a new approach to treat mood disorders. Elucidating how neurosteroids are distinguished from established GABA_AR-active drugs, e.g. benzodiazepines, may improve understanding of depressive disorders and aid drug development for psychiatric conditions. Here, we focus on research highlighting: (1) the acute interaction of neurosteroids with GABA_ARs incorporating the δ subunit (δ-GABA_AR) and (2) how neurosteroids may additionally act on a slower time scale to enhance expression of δ-GABA_ARs, thereby providing sustained therapeutic benefit.

Original language	English
Article number	100333
Pages (from-to)	1-9
Number of pages	9
Journal	Current Opinion in Endocrine and Metabolic Research
Volume	24
Early online date	20 Feb 2022
DOIs	https://doi.org/10.1016/j.coemr.2022.100333
Publication status	Published - Jun 2022

Keywords

Allopregnanolone
Brexanolone
GABA receptors
Major depressive disorder
Neurosteroids
Postpartum depression

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.coemr.2022.100333Licence: CC BY-NC-ND

Final published versionFinal published version, 543 KBLicence: UK Government Non-Commercial Licence

Cite this

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title = "The immediate and maintained effects of neurosteroids on GABAA receptors",

abstract = "Allopregnanolone is an endogenous neurosteroid that acts in a rapid non-genomic manner to enhance the function of the GABAA receptor (GABAAR), the major inhibitory receptor in the mammalian central nervous system (CNS). Consequently, allopregnanolone elicits anxiolytic, antidepressant, anticonvulsant, analgesic and sedative effects. Endogenous allopregnanolone influences neural inhibition and behaviour, with perturbed neurosteroid levels implicated in depressive disorders. The approval of brexanolone (an allopregnanolone formulation) to treat postpartum depression (PPD) has encouraged optimism that they may provide a new approach to treat mood disorders. Elucidating how neurosteroids are distinguished from established GABAAR-active drugs, e.g. benzodiazepines, may improve understanding of depressive disorders and aid drug development for psychiatric conditions. Here, we focus on research highlighting: (1) the acute interaction of neurosteroids with GABAARs incorporating the δ subunit (δ-GABAAR) and (2) how neurosteroids may additionally act on a slower time scale to enhance expression of δ-GABAARs, thereby providing sustained therapeutic benefit.",

keywords = "Allopregnanolone, Brexanolone, GABA receptors, Major depressive disorder, Neurosteroids, Postpartum depression",

author = "D. Belelli and Peters, {J. A.} and Phillips, {G. D.} and Lambert, {J. J.}",

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AU - Belelli, D.

AU - Peters, J. A.

AU - Phillips, G. D.

AU - Lambert, J. J.

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Y1 - 2022/6

N2 - Allopregnanolone is an endogenous neurosteroid that acts in a rapid non-genomic manner to enhance the function of the GABAA receptor (GABAAR), the major inhibitory receptor in the mammalian central nervous system (CNS). Consequently, allopregnanolone elicits anxiolytic, antidepressant, anticonvulsant, analgesic and sedative effects. Endogenous allopregnanolone influences neural inhibition and behaviour, with perturbed neurosteroid levels implicated in depressive disorders. The approval of brexanolone (an allopregnanolone formulation) to treat postpartum depression (PPD) has encouraged optimism that they may provide a new approach to treat mood disorders. Elucidating how neurosteroids are distinguished from established GABAAR-active drugs, e.g. benzodiazepines, may improve understanding of depressive disorders and aid drug development for psychiatric conditions. Here, we focus on research highlighting: (1) the acute interaction of neurosteroids with GABAARs incorporating the δ subunit (δ-GABAAR) and (2) how neurosteroids may additionally act on a slower time scale to enhance expression of δ-GABAARs, thereby providing sustained therapeutic benefit.

AB - Allopregnanolone is an endogenous neurosteroid that acts in a rapid non-genomic manner to enhance the function of the GABAA receptor (GABAAR), the major inhibitory receptor in the mammalian central nervous system (CNS). Consequently, allopregnanolone elicits anxiolytic, antidepressant, anticonvulsant, analgesic and sedative effects. Endogenous allopregnanolone influences neural inhibition and behaviour, with perturbed neurosteroid levels implicated in depressive disorders. The approval of brexanolone (an allopregnanolone formulation) to treat postpartum depression (PPD) has encouraged optimism that they may provide a new approach to treat mood disorders. Elucidating how neurosteroids are distinguished from established GABAAR-active drugs, e.g. benzodiazepines, may improve understanding of depressive disorders and aid drug development for psychiatric conditions. Here, we focus on research highlighting: (1) the acute interaction of neurosteroids with GABAARs incorporating the δ subunit (δ-GABAAR) and (2) how neurosteroids may additionally act on a slower time scale to enhance expression of δ-GABAARs, thereby providing sustained therapeutic benefit.

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