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Review
. 2023 Oct 20:17:1218737.
doi: 10.3389/fncir.2023.1218737. eCollection 2023.

GABAergic signaling in alcohol use disorder and withdrawal: pathological involvement and therapeutic potential

Ravinder Naik Dharavath  1 , Celeste Pina-Leblanc  1   2 , Victor M Tang  1   3   4   5   6   7 , Matthew E Sloan  1   2   4   5   8   6   7 , Yuliya S Nikolova  1   3 , Peter Pangarov  1 , Anthony C Ruocco  1   3   9   10 , Kevin Shield  7 , Daphne Voineskos  1   3   9 , Daniel M Blumberger  1   3   9 , Isabelle Boileau  1   2   3   11 , Nikki Bozinoff  1   12 , Philip Gerretsen  1   3   6   11 , Erica Vieira  1   3 , Osnat C Melamed  1   12 , Etienne Sibille  1   2   3 , Lena C Quilty  1   3 , Thomas D Prevot  1   3
Affiliations
Review

GABAergic signaling in alcohol use disorder and withdrawal: pathological involvement and therapeutic potential

Ravinder Naik Dharavath et al. Front Neural Circuits. .

Abstract

Alcohol is one of the most widely used substances. Alcohol use accounts for 5.1% of the global disease burden, contributes substantially to societal and economic costs, and leads to approximately 3 million global deaths yearly. Alcohol use disorder (AUD) includes various drinking behavior patterns that lead to short-term or long-lasting effects on health. Ethanol, the main psychoactive molecule acting in alcoholic beverages, directly impacts the GABAergic system, contributing to GABAergic dysregulations that vary depending on the intensity and duration of alcohol consumption. A small number of interventions have been developed that target the GABAergic system, but there are promising future therapeutic avenues to explore. This review provides an overview of the impact of alcohol on the GABAergic system, the current interventions available for AUD that target the GABAergic system, and the novel interventions being explored that in the future could be included among first-line therapies for the treatment of AUD.

Keywords: GABA; alcohol use disorders; clinical trials; integrative approach; interventions; pharmacotherapy; translational; unmet need.

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Conflict of interest statement

TP receives compensation for consulting work from Damona Pharmaceutical Inc., a biotech company developing GABAergic molecules for the treatment of cognitive dysfunctions in depression. ES is co-founder, CEO and CSO of Damona Pharmaceutical Inc. DB receives research support from CIHR, NIH, Brain Canada, and the Temerty Family through the CAMH Foundation. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. and has been the site principal investigator for three sponsor-initiated studies for Brainsway Ltd. DB also received in-kind equipment support from Magventure for 3 investigator-initiated studies. DB received medication supplies for an investigator-initiated trial from Indivior. DB has participated in one Scientific Advisory Board Meeting for Janssen and one meeting for Welcony Inc. DV holds the Labatt Family Professorship in Depression Biology, a University Named Professorship at the University of Toronto. She receives research support from CIHR, NIH, the Centre for Addiction and Mental Health (CAMH), University Hospital Network (UHN) and the Department of Psychiatry at the University of Toronto. DV declares no biomedical interests or conflicts. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Brain circuits affected by alcohol consumption in the context of acute or prolonged exposure. (A) Alcohol induces changes in neutrotransmitters including glutamate (green), GABA (orange), dopamine (blue), serotonin (yellow), opioid (grey) and acetylcholine (purple), in various brain regions. (B) During acute alcohol consumption, ethanol induces a decrease in glutamatergic activity and an increased of GABAergic, dopaminergic, serotoninergic, opioid and cholinergic systems. With prolonged alcohol consumption, the different systems establish themselves at a new baseline level. To experience the effect of alcohol, individuals have to further increase their consumption leading to disinhibition and euphoria, but increasing the risk of AUD and dependence. During withdrawal, glutamatergic activity increases above the newly-set baseline, while GABAergic, dopaminergic, serotoninergic, opioid and cholinergic activity decrease, causing withdrawal symptoms, craving and seeking behaviors. Arrows in panel A shows direction of the projections between brain regions. NAc, Nucleus accumbens; PFC, Prefrontal cortex; VTA, Ventral tegmental area.
Figure 2
Figure 2
GABA receptor subtypes involved in modulation of ethanol. (A) Molecular structures of γ- and δ- subunit-containing GABAA receptors. (B) Ligand-specific binding sites of γ- and δ- subunit-containing GABAA receptors. (C) Molecular structure and downstream signaling of GABAB receptors. α, β, γ, δ, subunits of GABAA receptor; Cl-, Chloride ion; GABA, Gamma-aminobutyric acid; NMDA-R, N-Methyl-D-aspartic acid receptor; K+, Potassium ion; Ca+2, Calcium ion; PKA, Protein kinase A; cAMP, Cyclic Adenosine monophosphate; ATP, Adenosine triphosphate; AC, Adenylyl cyclase.
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