Potential of GABAB Receptor Positive Allosteric Modulators in the Treatment of Alcohol Use Disorder
Abstract
The orthosteric γ-aminobutyric acid B (GABA B) receptor agonist baclofen is currently considered a therapeutic option for alcohol use disorder (AUD); however, the safety profile of baclofen is a concern, thus arousing interest in the positive allosteric modulators (PAMs) of the GABA B receptor (GABA B PAMs), a new class of ligands expected to possess a better safety profile. The present paper summarizes the several lines of experimental evidence indicating the ability of GABA B PAMs to inhibit multiple alcohol-motivated behaviors in rodents. All GABA B PAMs tested to date have invariably been reported to reduce, or even suppress, excessive alcohol drinking, relapse- and binge-like drinking, operant oral alcohol self-administration, reinstatement of alcohol seeking, and alcohol-induced locomotor stimulation and conditioned place preference in rats and mice. The use of validated animal models of several aspects of AUD confers translational value to these findings. The reducing effects of GABA B PAMs on alcohol-motivated behaviors (1) occurred at doses largely lower than those inducing sedation, suggesting that GABA B PAMs may possess, if compared with baclofen, a higher therapeutic index and a more favorable safety profile, and (2) were often not associated with reductions on other non-drug consummatory behaviors. Additional findings with therapeutic potential were (1) the lack of tolerance, after repeated treatment, to the reducing effect of GABA B PAMs on alcohol drinking and self-administration; (2) the efficacy of GABA B PAMs after intragastric administration; and (3) the ability of GABA B PAMs to selectively potentiate the suppressing effect of baclofen on alcohol self-administration. The recent transition of the first GABA B PAMs to the initial steps of clinical testing makes investigation of the efficacy of GABA B PAMs in AUD patients a feasible option.
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ASP8062 is a novel agent that acts as a positive allosteric modulator of GABA-B, similar to baclofen, which is an orthosteric GABA-B receptor agonist.
“ASP8062 is a novel agent which acts as a positive allosteric modulator of GABA-B, similar to baclofen, which is an orthosteric GABA-B receptor agonist [58].”
From A Narrative Review of Current and Emerging Trends in the Treatment of Alcohol Use Disorder (2024) · cites this paper as [58]
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Lobina, C., Maccioni, P., Lorrai, I., Zaru, A., Collu, M., Carai, M. A. M., Brizzi, A., Mugnaini, C., Gessa, G. L., Corelli, F., et al. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.113045 · Cited by 6 · see citing works
Self-citationMaccioni, P., Kaczanowska, K., McDonald, P. H., & Colombo, G. (2022) · Alcohol and Alcoholism · doi:10.1093/alcalc/agac026 · Cited by 6 · see citing works
Self-citationColombo, G. (2024) · Alcohol and Alcoholism · doi:10.1093/alcalc/agae018 · Cited by 5 · see citing works
Self-citationLorrai, I., Shankula, C. A., Gaytan, J. M., Maccioni, R., Lobina, C., Maccioni, P., Brizzi, A., Mugnaini, C., Gessa, G. L., Sanna, P. P., et al. (2022) · The American Journal of Drug and Alcohol Abuse · doi:10.1080/00952990.2022.2116713 · Cited by 4 · see citing works
Self-citationAnorectic effect of COR659 in a rat model of overeating
Maccioni, P., Mugnaini, C., Carai, M. A. M., Gessa, G. L., Corelli, F., & Colombo, G. (2023) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000751 · Cited by 2 · see citing works
Self-citationMaccioni, P., Lorrai, I., Carai, M. A. M., Gessa, G. L., & Colombo, G. (2021) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000668 · Cited by 1 · see citing works
Self-citationNuclear power, technology, and environmental law
Gofman, J. W., & Tamplin, A. R. (1971) · OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) · Cited by 1 · see citing works
G protein-coupled receptor (GPCR)-dependent transduction
Andersen, H. K., & Laprairie, R. B. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-819771-4.00010-5
Reducing the harms of alcohol: nutritional interventions and functional alcohol alternatives
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Recent Advances on the Chemistry of GABAB Receptor Allosteric Modulators
Mugnaini, C., & Corelli, F. (2024) · The Receptors · doi:10.1007/978-3-031-67148-7_8
Maccioni, P., & Colombo, G. (2024) · The Receptors · doi:10.1007/978-3-031-67148-7_12
Self-citationLorrai, I., Maccioni, R., Gaytan, J. M., Yin, S.-C., Shankula, C. A., Lobina, C., Maccioni, P., Sanna, P. P., & Colombo, G. (2026) · The American Journal of Drug and Alcohol Abuse · doi:10.1080/00952990.2025.2596377
Self-citationChen, G., Huang, X., Yu, J., Zhang, Y., Wang, Z., Li, X., 李芳云, Wang, X., Chen, P., Chen, R., et al. (2026) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2026.111877
- Authors
- Maccioni, P., & Colombo, G.
- Affiliations
- National Research Council (IT)
- Corresponding author
- Maccioni, Paola
- Venue
- CNS Drugs
- Published
- 2019-01-02
- Volume
- 33
- Issue
- 2
- Pages
- 107-123
- ISSN
- 1172-7047 (ISSN-L)
- 1179-1934
- OpenAlex
- W2907707759
- Cited by
- 40
- References
- 69
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 8 · 2023: 5 · 2022: 5 · 2021: 11 · 2020: 5 · 2019: 2
- FWCI
- 2.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- CNS Drugs (publishedVersion)
- PubMed (publishedVersion)
- CNR ExploRA (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- GABAB receptors, positive allosteric modulators, alcoholism, baclofen, alcohol self-administration, alcohol relapse, binge drinking, conditioned place preference, tolerance (pharmacology and immunology), therapeutic index, drug safety, animal models of alcoholism
- MeSH terms
- Allosteric Regulation, Animals, Conditioning, Psychological, Humans, Motor Activity, Reinforcement, Psychology, Molecular Structure, Receptors, GABA-B, Alcohol-Related Disorders, GABA-B Receptor Agonists
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