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

Bernhard Luscher; Jamie L Maguire; Uwe Rudolph; Etienne Sibille

doi:10.1016/j.tips.2023.06.009

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

Trends Pharmacol Sci. 2023 Sep;44(9):586-600. doi: 10.1016/j.tips.2023.06.009. Epub 2023 Aug 3.

Authors

Bernhard Luscher¹, Jamie L Maguire², Uwe Rudolph³, Etienne Sibille⁴

Affiliations

¹ Department of Biology, Pennsylvania State University, University Park, PA 16802, USA; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA; Department of Psychiatry, Pennsylvania State University, University Park, PA 16802, USA; Penn State Neuroscience Institute, Pennsylvania State University, University Park, PA 16802, USA.
² Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA.
³ Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA. Electronic address: urudolph@illinois.edu.
⁴ Campbell Family Mental Health Research Institute of the Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.

Abstract

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 GABA_A receptor (GABA_AR) system as a target for novel antidepressants and discusses the mechanisms by which modulation of δ-containing GABA_ARs with neuroactive steroids (NASs) or of α5-containing GABA_ARs results in antidepressant or antidepressant-like actions and discusses clinical data on NASs. Moreover, a potential mechanism by which α5-GABA_AR-positive allosteric modulators (PAMs) may improve cognitive deficits in depression is presented.

Keywords: GABA(A) receptor; Gabra5; Gabrd; chronic stress; cognition; depression; emotion; neurosteroids.

Publication types

Review
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Antidepressive Agents / pharmacology
Antidepressive Agents / therapeutic use
Cognition
Depression / drug therapy
Depressive Disorder, Major* / drug therapy
Humans
Receptors, GABA-A*
gamma-Aminobutyric Acid

Substances

Receptors, GABA-A
Antidepressive Agents
gamma-Aminobutyric Acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding