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bioRxiv · 10.1101/2024.09.13.612946

Operant alcohol self-administration targets GluA2-containing AMPAR expression and synaptic activity in the nucleus accumbens in a manner that drives the reinforcing properties of the drug

Faccidomo, S.·Saunders, B.·May, A.·Eastman, V.·Kim, M.·Taylor, S.·Hoffman, J.·McElligott, Z.·Hodge, C. W.
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Abstract

Rationale: The positive reinforcing effects of alcohol (ethanol) drive its 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 ethanols 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 ethanols reinforcing effects in male C57BL/6J 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.

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Faccidomo, S., Saunders, B., May, A., Eastman, V., Kim, M., Taylor, S., Hoffman, J., McElligott, Z., Hodge, C. W.. 2024-09-14. Operant alcohol self-administration targets GluA2-containing AMPAR expression and synaptic activity in the nucleus accumbens in a manner that drives the reinforcing properties of the drug. https://doi.org/10.1101/2024.09.13.612946

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