Shillinglaw Joel E, Morrisett Richard A, Mangieri Regina A
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, United States.
Front Pharmacol. 2018 Dec 18;9:1458. doi: 10.3389/fphar.2018.01458. eCollection 2018.
The agranular insular cortex (AIC) has recently been investigated by the alcohol field because of its connectivity to and modulatory control over limbic and brainstem regions implicated in alcohol use disorder (AUD), and because it has shown involvement in animal models of alcohol drinking. Despite evidence of AIC involvement in AUD, there has not yet been an examination of whether ethanol modulates glutamatergic and γ-amino-butyric acid (GABA)ergic synaptic transmission and plasticity in the AIC. Characterizing how the synaptic transmission and plasticity states of AIC cortical processing neurons are modulated by acute ethanol will likely reveal the molecular targets by which chronic ethanol alters AIC function as alcohol drinking transitions from controlled to problematic. Therefore, we collected brain slices from ethanol-naïve adult male mice, obtained whole-cell recording configuration in layer 2/3 AIC pyramidal neurons, and bath-applied ethanol at pharmacologically relevant concentrations during electrophysiological assays of glutamatergic and GABAergic synaptic transmission and plasticity. We found that ethanol inhibited electrically evoked N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory post-synaptic currents (EPSCs) in a concentration-related fashion, and had little effect on evoked α-amino-3-hydrox-5-methylisoxazole-4-propionic acid-type receptor (AMPAR)-mediated EPSCs. Ethanol had no effect on spontaneous excitatory post-synaptic currents (sEPSCs) or inhibitory GABAR-mediated post-synaptic currents (sIPSCs). We found that synaptic conditioning (low-frequency stimulation for 15 min at 1 Hz) induced a form of long-term depression (LTD) of evoked AMPAR-mediated EPSCs. The ability to induce LTD was inhibited by a non-selective NMDAR antagonist (DL-2-amino-5-phosphonovaleric acid), and also by acute, intoxicating concentrations of ethanol. Taken together these data suggest that the glutamate, but not GABA system in the AIC is uniquely sensitive to ethanol, and that in particular NMDAR-mediated processes in the AIC may be disrupted by pharmacologically relevant concentrations of ethanol.
由于无颗粒岛叶皮质（AIC）与酒精使用障碍（AUD）相关的边缘系统和脑干区域存在连接并对其具有调节控制作用，且已显示其参与酒精摄入的动物模型，因此酒精研究领域最近对其进行了调查。尽管有证据表明AIC参与了AUD，但尚未有人研究乙醇是否调节AIC中的谷氨酸能和γ-氨基丁酸（GABA）能突触传递及可塑性。明确急性乙醇如何调节AIC皮质处理神经元的突触传递和可塑性状态，可能会揭示慢性乙醇在饮酒从可控转变为问题行为时改变AIC功能的分子靶点。因此，我们从未接触过乙醇的成年雄性小鼠中采集脑片，在AIC第2/3层锥体神经元中获得全细胞记录配置，并在谷氨酸能和GABA能突触传递及可塑性的电生理测定过程中，以药理学相关浓度对其进行乙醇灌浴。我们发现乙醇以浓度相关的方式抑制电诱发的N-甲基-D-天冬氨酸受体（NMDAR）介导的兴奋性突触后电流（EPSC），而对诱发的α-氨基-3-羟基-5-甲基异恶唑-4-丙酸型受体（AMPAR）介导的EPSC影响很小。乙醇对自发性兴奋性突触后电流（sEPSC）或抑制性GABAR介导的突触后电流（sIPSC）没有影响。我们发现突触条件化（以1 Hz频率进行15分钟的低频刺激）可诱导诱发的AMPAR介导的EPSC出现一种形式的长时程抑制（LTD）。诱导LTD的能力受到非选择性NMDAR拮抗剂（DL-2-氨基-5-磷酸戊酸）以及急性中毒浓度乙醇的抑制。综合这些数据表明，AIC中的谷氨酸系统而非GABA系统对乙醇具有独特的敏感性，并且AIC中特别是NMDAR介导的过程可能会被药理学相关浓度的乙醇破坏。
