GABAA receptors as targets for treating affective and cognitive symptoms of depression

Bernhard Luscher, Jamie L. Maguire, Uwe Rudolph, Etienne Sibille

Research output: Contribution to journalReview articlepeer-review


In the past 20 years, our understanding of the pathophysiology of depression has evolved from a focus on an imbalance of monoaminergic neurotransmitters to a multifactorial picture including an improved understanding of the role of glutamatergic excitatory and GABAergic inhibitory neurotransmission. FDA-approved treatments targeting the glutamatergic [esketamine for major depressive disorder (MDD)] and GABAergic (brexanolone for peripartum depression) systems have become available. This review focuses on the GABAA receptor (GABAAR) system as a target for novel antidepressants and discusses the mechanisms by which modulation of δ-containing GABAARs with neuroactive steroids (NASs) or of α5-containing GABAARs results in antidepressant or antidepressant-like actions and discusses clinical data on NASs. Moreover, a potential mechanism by which α5-GABAAR-positive allosteric modulators (PAMs) may improve cognitive deficits in depression is presented.

Original languageEnglish (US)
Pages (from-to)586-600
Number of pages15
JournalTrends in Pharmacological Sciences
Issue number9
StatePublished - Sep 2023


  • GABA receptor
  • Gabra5
  • Gabrd
  • chronic stress
  • cognition
  • depression
  • emotion
  • neurosteroids

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology


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