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Modulators of GABAA receptor-mediated inhibition in the treatment of neuropsychiatric disorders: past, present, and future

Neuropsychopharmacology volume 49, pages 83–95 (2024)Cite this article

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Abstract

The predominant inhibitory neurotransmitter in the brain, γ-aminobutyric acid (GABA), acts at ionotropic GABAA receptors to counterbalance excitation and regulate neuronal firing. GABAA receptors are heteropentameric channels comprised from subunits derived from 19 different genes. GABAA receptors have one of the richest and well-developed pharmacologies of any therapeutic drug target, including agonists, antagonists, and positive and negative allosteric modulators (PAMs, NAMs). Currently used PAMs include benzodiazepine sedatives and anxiolytics, barbiturates, endogenous and synthetic neurosteroids, and general anesthetics. In this article, I will review evidence that these drugs act at several distinct binding sites and how they can be used to alter the balance between excitation and inhibition. I will also summarize existing literature regarding (1) evidence that changes in GABAergic inhibition play a causative role in major depression, anxiety, postpartum depression, premenstrual dysphoric disorder, and schizophrenia and (2) whether and how GABAergic drugs exert beneficial effects in these conditions, focusing on human studies where possible. Where these classical therapeutics have failed to exert benefits, I will describe recent advances in clinical and preclinical drug development. I will also highlight opportunities to advance a generation of GABAergic therapeutics, such as development of subunit-selective PAMs and NAMs, that are engendering hope for novel tools to treat these devastating conditions.

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Fig. 1: Images of adult human brain sections showing in situ hybridization for various GABAA receptor subunits.
Fig. 2: Localization of α5 subunit-containing GABAA receptors.

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Acknowledgements

I am grateful to the members of my laboratory and my collaborators who have taught me much about both GABA actions and drug development, Drs. J. Atack, R. Berman, J. Fischell, T. Gould, M. Kvarta, T. LeGates, T. Troppoli, and P. Zanos. Portions of my work with α5 NAMs have been supported by the Kahlert Foundation and the NIH (R01 MH086828).

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    Scott M. Thompson

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The University of Maryland Baltimore has patents, on which I am listed as an inventor, covering the use of α5-selective NAMs to treat psychiatric disease.

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Thompson, S.M. Modulators of GABAA receptor-mediated inhibition in the treatment of neuropsychiatric disorders: past, present, and future. Neuropsychopharmacol. 49, 83–95 (2024). https://doi.org/10.1038/s41386-023-01728-8

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