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

Sara Faccidomo; Briana L Saunders; Ashley M May; Vallari R Eastman; Michelle Kim; Seth M Taylor; Jessica L Hoffman; Zoé A McElligott; Clyde W Hodge

doi:10.1007/s00213-024-06740-4

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

Psychopharmacology (Berl). 2024 Dec 23. doi: 10.1007/s00213-024-06740-4. Online ahead of print.

Authors

Sara Faccidomo^{1

2}, Briana L Saunders¹, Ashley M May¹, Vallari R Eastman¹, Michelle Kim¹, Seth M Taylor¹, Jessica L Hoffman¹, Zoé A McElligott^{1

2

3}, Clyde W Hodge^{4

5

6}

Affiliations

¹ Bowles Center for Alcohol Studies, Department of Psychiatry, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
² Department of Psychiatry, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
³ Department of Pharmacology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
⁴ Bowles Center for Alcohol Studies, Department of Psychiatry, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. chodge@med.unc.edu.
⁵ Department of Psychiatry, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. chodge@med.unc.edu.
⁶ Department of Pharmacology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. chodge@med.unc.edu.

PMID: 39714485
DOI: 10.1007/s00213-024-06740-4

Abstract

Rationale: The 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.

Objective: This 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.

Results: Sucrose-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.

Conclusions: Ethanol 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.

Keywords: AMPA; Alcohol; Basolateral amygdala; GluA2; NSF; Nucleus accumbens; Self-administration.

Abstract

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