Relating neurosteroid modulation of inhibitory neurotransmission to behaviour

Delia Belelli, Grant D. Phillips, John R. Atack, Jeremy J. Lambert (Lead / Corresponding author)

Research output: Contribution to journalReview articlepeer-review

3 Citations (Scopus)

Abstract

Studies in the 1980s revealed endogenous metabolites of progesterone and deoxycorticosterone to be potent, efficacious, positive allosteric modulators (PAMs) of the GABA A receptor (GABA AR). The discovery that such steroids are locally synthesised in the central nervous system (CNS) promoted the thesis that neural inhibition in the CNS may be “fine-tuned” by these neurosteroids to influence behaviour. In preclinical studies, these neurosteroids exhibited anxiolytic, anticonvulsant, analgesic and sedative properties and, at relatively high doses, induced a state of general anaesthesia, a profile consistent with their interaction with GABA ARs. However, realising the therapeutic potential of either endogenous neurosteroids or synthetic “neuroactive” steroids has proven challenging. Recent approval by the Food and Drug Administration of the use of allopregnanolone (brexanolone) to treat postpartum depression has rekindled enthusiasm for exploring their potential as new medicines. Although neurosteroids are selective for GABA ARs, they exhibit little or no selectivity across the many GABA AR subtypes. Nevertheless, a relatively minor population of receptors incorporating the δ-subunit (δ-GABA ARs) appears to be an important contributor to their behavioural effects. Here, we consider how neurosteroids acting upon GABA ARs influence neuronal signalling, as well as how such effects may acutely and persistently influence behaviour, and explore the case for developing selective PAMs of δ-GABA AR subtypes for the treatment of psychiatric disorders.

Original languageEnglish
Article numbere13045
Number of pages12
JournalJournal of Neuroendocrinology
Volume34
Issue number2
Early online date20 Sep 2021
DOIs
Publication statusPublished - 23 Feb 2022

Keywords

  • GABA receptor
  • allopregnanolone
  • major depressive disorder
  • neurosteroid
  • postpartum depression

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