ArticlePsychopharmacology2025
Ethanol self-administration targets GluA2-containing AMPA receptor expression and synaptic activity in the nucleus accumbens in a manner that drives the positive reinforcing properties of the drug.
Article in Psychopharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Ethanol Self-Administration Reduces mGlu2/3 Protein Expression in the Nucleus Accumbens and mGlu2/3 Activation Suppresses Binge Drinking in Male Mice.Alcohol, clinical & experimental research · 2026Article
- Transmembrane AMPA receptor regulatory protein TARP ɣ-8 is a target of ethanol that regulates self-administration and relapse in mice.Psychopharmacology · 2026Article
- Glutamate delta-1 receptors regulate a tonic excitatory conductance in the mouse bed nucleus of the stria terminalis and influence neuronal function.Psychopharmacology · 2026Article
- Taste matters: lessons learned in translating a conditioned drug cue reactivity paradigm from rodents to humans.Frontiers in psychology · 2026Article
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Abstract
rationaleThe positive reinforcing effects of alcohol (ethanol) drive repetitive use and contribute to alcohol use disorder (AUD). Ethanol alters the expression of glutamate AMPA receptor (AMPAR) subunits in reward-related brain regions, but the extent to which this effect regulates ethanol's reinforcing properties is unclear.
objectiveThis study investigates whether ethanol self-administration changes AMPAR subunit expression and synaptic activity in the nucleus accumbens core (AcbC) to regulate ethanol's reinforcing effects in male C57BL/6 J mice.
resultsSucrose-sweetened ethanol self-administration (0.81 g/kg/day) increased AMPAR GluA2 protein expression in the AcbC, without effect on GluA1, compared to sucrose-only controls. Infusion of myristoylated Pep2m in the AcbC, which blocks GluA2 binding to N-ethylmaleimide-sensitive fusion protein (NSF) and reduces GluA2-containing AMPAR activity, reduced ethanol-reinforced responding without affecting sucrose-only self-administration or motor activity. Antagonizing GluA2-lacking AMPARs, through AcbC infusion of NASPM, had no effect on ethanol self-administration. AcbC neurons receiving projections from the basolateral amygdala (BLA) showed increased sEPSC area under the curve (a measurement of charge transfer) and slower decay kinetics in ethanol self-administering mice as compared to sucrose. Optogenetic activation of these neurons revealed an ethanol-enhanced AMPA/NMDA ratio and significantly reduced paired-pulse ratio, suggesting elevated GluA2 contributions specifically within the BLA➔AcbC pathway.
conclusionsEthanol use upregulates GluA2 protein expression in the AcbC and AMPAR synaptic activity in AcbC neurons receiving BLA projections and enhances synaptic plasticity directly within the BLA➔AcbC circuit. GluA2-containing AMPAR activity in the AcbC regulates the positive reinforcing effects of ethanol through an NSF-dependent mechanism, highlighting a potential therapeutic target in AUD.
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