Institute for Neuroscience, The University of Texas at Austin, Austin, Texas, USA.
The College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA.
Addict Biol. 2018 Mar;23(2):689-698. doi: 10.1111/adb.12526. Epub 2017 Jun 28.
The nucleus accumbens (NAc) is a critical component of the mesocorticolimbic system and is involved in mediating the motivational and reinforcing aspects of ethanol consumption. Chronic intermittent ethanol (CIE) exposure is a reliable model to induce ethanol dependence and increase volitional ethanol consumption in mice. Following a CIE-induced escalation of ethanol consumption, NMDAR (N-methyl-D-aspartate receptor)-dependent long-term depression in D1 dopamine receptor expressing medium spiny neurons of the NAc shell was markedly altered with no changes in plasticity in D1 dopamine receptor medium spiny neurons from the NAc core. This disruption of plasticity persisted for up to 2 weeks after cessation of ethanol access. To determine if changes in AMPA receptor (AMPAR) composition contribute to this ethanol-induced neuroadaptation, we monitored the rectification of AMPAR excitatory postsynaptic currents (EPSCs). We observed a marked decrease in the rectification index in the NAc shell, suggesting the presence of GluA2-lacking AMPARs. There was no change in the amplitude of spontaneous EPSCs (sEPSCs), but there was a transient increase in sEPSC frequency in the NAc shell. Using the paired pulse ratio, we detected a similar transient increase in the probability of neurotransmitter release. With no change in sEPSC amplitude, the change in the rectification index suggests that GluA2-containing AMPARs are removed and replaced with GluA2-lacking AMPARs in the NAc shell. This CIE-induced alteration in AMPAR subunit composition may contribute to the loss of NMDAR-dependent long-term depression in the NAc shell and therefore may constitute a critical neuroadaptive response underlying the escalation of ethanol intake in the CIE model.
伏隔核（NAc）是中脑边缘系统的关键组成部分，参与介导乙醇消费的动机和强化方面。慢性间歇性乙醇（CIE）暴露是诱导乙醇依赖和增加小鼠自愿性乙醇消费的可靠模型。在 CIE 诱导的乙醇消费增加之后，NAc 壳中的表达 D1 多巴胺受体的中脑边缘神经元中的 NMDAR（N-甲基-D-天冬氨酸受体）依赖性长时程抑郁显著改变，而 NAc 核中的 D1 多巴胺受体中脑边缘神经元的可塑性没有变化。这种可塑性的破坏在停止乙醇接触后持续长达 2 周。为了确定 AMPA 受体（AMPAR）组成的变化是否有助于这种乙醇诱导的神经适应，我们监测了 AMPAR 兴奋性突触后电流（EPSC）的整流。我们观察到 NAc 壳中的整流指数明显降低，表明存在缺乏 GluA2 的 AMPAR。自发 EPSC（sEPSC）的幅度没有变化，但 NAc 壳中的 sEPSC 频率短暂增加。使用成对脉冲比，我们检测到 NAc 壳中神经递质释放概率的类似短暂增加。由于 sEPSC 幅度没有变化，整流指数的变化表明 NAc 壳中含有 GluA2 的 AMPAR 被去除并被缺乏 GluA2 的 AMPAR 取代。这种 CIE 诱导的 AMPAR 亚基组成的改变可能导致 NAc 壳中 NMDAR 依赖性长时程抑郁的丧失，因此可能构成 CIE 模型中乙醇摄入增加的关键神经适应反应。
