Cited by 197Neuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on BehaviorSubstance Abuse Treatment and Outcomes

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Glutamatergic targets for new alcohol medications

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Holmes, Andrew, Spanagel, Rainer, Krystal, John H.·2013·Psychopharmacology

DOI 10.1007/s00213-013-3226-2PMC PMC3811052

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Abstract

Rationale An increasingly compelling literature points to a major role for the glutamate system in mediating the effects of alcohol on behavior and the pathophysiology of alcoholism. Preclinical studies indicate that glutamate signaling mediates certain aspects of ethanol's intoxicating and rewarding effects, and undergoes adaptations following chronic alcohol exposure that may contribute to the withdrawal, craving and compulsive drug-seeking that drive alcohol abuse and alcoholism.Objectives We discuss the potential for targeting the glutamate system as a novel pharmacotherapeutic approach to treating alcohol use disorders, focusing on five major components of the glutamate system: the N-methyl-D-aspartate (NMDA) receptor and specific NMDA subunits, the glycineB site on the NMDA receptors (NMDAR), L-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid ionotropic (AMPA) and kainate (KAR) receptors, metabotropic receptors (mGluR), and glutamate transporters.Results Chronic alcohol abuse produces a hyperglutamatergic state, characterized by elevated extracellular glutamate and altered glutamate receptors and transporters. Pharmacologically manipulating glutamatergic neurotransmission alters alcohol-related behaviors including intoxication, withdrawal, and alcohol-seeking, in rodents and human subjects. Blocking NMDA and AMPA receptors reduces alcohol consumption in rodents, but side-effects may limit this as a therapeutic approach. Selectively targeting NMDA and AMPA receptor subunits (e.g., GluN2B, GluA3), or the NMDAR glycineB site offers an alternative approach. Blocking mGluR5 potently affects various alcohol-related behaviors in rodents, and mGluR2/3 agonism also suppresses alcohol consumption. Finally, glutamate transporter upregulation may mitigate behavioral and neurotoxic sequelae of excess glutamate caused by alcohol.Conclusions Despite the many challenges that remain, targeting the glutamate system offers genuine promise for developing new treatments for alcoholism.

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Authors: Holmes, A., Spanagel, R., & Krystal, J. H.
Affiliations: National Institutes of Health (US)
Heidelberg University (DE)
Yale University (US)
Corresponding author: Holmes, Andrew
ORCID: Holmes, Andrew
Spanagel, Rainer
Krystal, John H.
Venue: Psychopharmacology
Publisher: Springer Science and Business Media LLC
Published: 2013-09-01
Volume: 229
Issue: 3
Pages: 539-554
ISSN: 0033-3158 (ISSN-L)
1432-2072
DOI: 10.1007/s00213-013-3226-2
PMC: PMC3811052
OpenAlex: W2104412023
Cited by: 197
References: 221
Citations by year: 2026: 7 · 2025: 14 · 2024: 10 · 2023: 5 · 2022: 7 · 2021: 15 · 2020: 16 · 2019: 15 · 2018: 22 · 2017: 14 · 2016: 25 · 2015: 29 · 2014: 17 · 2013: 1
FWCI: 2.44
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Psychopharmacology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Institute on Alcohol Abuse and Alcoholism (P50AA012870, ZIAAA000411)
National Center for Research Resources (UL1RR024139)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
Keywords: glutamatergic system, alcoholism, alcoholism pharmacotherapy, NMDA receptor, NMDA receptor glycine site, AMPA receptors, kainate receptors, metabotropic glutamate receptors, mGluR5, glutamate transporters, GluN2B, GluA3, alcohol withdrawal, alcohol craving, alcohol seeking, chronic ethanol exposure, glutamate excitotoxicity
MeSH terms: Alcoholism, Animals, Humans, Substance Withdrawal Syndrome, Receptors, N-Methyl-D-Aspartate, Receptors, AMPA, Kainic Acid Receptors, Glutamic Acid, Protein Subunits, Molecular Targeted Therapy, Drug-Seeking Behavior

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Glutamatergic targets for new alcohol medications

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