Faccidomo Sara, Saunders Briana L, May Ashley M, Eastman Vallari R, Kim Michelle, Taylor Seth M, Hoffman Jessica L, McElligott Zoé A, Hodge Clyde W
Bowles Center for Alcohol Studies, Department of Psychiatry, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Department of Psychiatry, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Psychopharmacology (Berl). 2025 Jun;242(6):1437-1452. doi: 10.1007/s00213-024-06740-4. Epub 2024 Dec 23.
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.
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.
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.
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.
酒精（乙醇）的正性强化作用促使其反复使用，并导致酒精使用障碍（AUD）。乙醇会改变奖赏相关脑区中谷氨酸AMPA受体（AMPAR）亚基的表达，但这种作用调节乙醇强化特性的程度尚不清楚。
本研究调查乙醇自我给药是否会改变雄性C57BL/6 J小鼠伏隔核核心（AcbC）中AMPAR亚基表达和突触活性，以调节乙醇的强化作用。
与仅给予蔗糖的对照组相比，蔗糖加乙醇自我给药（0.81 g/kg/天）增加了AcbC中AMPAR GluA2蛋白表达，而对GluA1无影响。在AcbC中注入肉豆蔻酰化的Pep2m，可阻断GluA2与N-乙基马来酰亚胺敏感融合蛋白（NSF）的结合并降低含GluA2的AMPAR活性，从而降低乙醇强化反应，而不影响仅给予蔗糖的自我给药或运动活性。通过在AcbC中注入NASPM拮抗缺乏GluA2的AMPARs，对乙醇自我给药没有影响。与蔗糖组相比，接受基底外侧杏仁核（BLA）投射的AcbC神经元在乙醇自我给药小鼠中显示出曲线下sEPSC面积增加（电荷转移的一种测量方法）和衰减动力学减慢。对这些神经元进行光遗传学激活显示乙醇增强了AMPA/NMDA比值，并显著降低了配对脉冲比率，表明GluA2在BLA➔AcbC通路中贡献增加。
乙醇使用上调了AcbC中GluA2蛋白表达以及接受BLA投射的AcbC神经元中的AMPAR突触活性，并直接增强了BLA➔AcbC回路内的突触可塑性。AcbC中含GluA2的AMPAR活性通过依赖NSF的机制调节乙醇的正性强化作用，突出了AUD的一个潜在治疗靶点。
