Modulation of native and recombinant GABAA receptors by endogenous and synthetic neuroactive steroids

Jeremy J. Lambert (Lead / Corresponding author), Delia Belelli, Sarah C. Harney, John A. Peters, Bruno G. Frenguelli

Research output: Contribution to journalReview article

130 Citations (Scopus)

Abstract

Upon administration, certain pregnane steroids produce clear behavioural effects including, anxiolysis, sedation, analgesia, anaesthesia and are anti-convulsant. This behavioural profile is characteristic of compounds that act to enhance the actions of GABA acting at the GABAA receptor. In agreement, numerous studies have now demonstrated these steroids to be potent, positive allosteric modulators of the GABAA receptor. The pregnane steroids are synthesized in the periphery by endocrine glands such as the adrenals and the ovaries, but are also made by neurons and glial cells in the central nervous system itself. Hence, these compounds could play both an endocrine and a paracrine role to influence neuronal excitability by promoting inhibition. Here we review evidence that the pregnane steroids are highly selective and extremely potent GABAA receptor modulators and that their effects at 'physiological' concentrations (low nanomolar) may be influenced by the subunit composition of the GABAA receptor. This feature may underlie recent findings demonstrating the effects of the neurosteroids on inhibitory synaptic transmission to be brain region dependent, although recent reports suggest that phosphorylation mechanisms may additionally influence neurosteroid sensitivity of the GABAA receptor. Numerous synthetic steroids have been synthesized in an attempt to therapeutically exploit the behavioural effects of the pregnane steroids and progress with this approach will be discussed. However, the demonstration that the steroids may be made within the central nervous system offers the alternative strategy of targeting the enzymes that synthesize/metabolise the neurosteroids to exploit this novel endocrine/paracrine interaction.

Original languageEnglish
Pages (from-to)68-80
Number of pages13
JournalBrain Research Reviews
Volume37
Issue number1-3
DOIs
Publication statusPublished - Nov 2001

Keywords

  • GABA
  • GABA receptor
  • Neuroactive steroids
  • Transmitter-gated ion channel

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