Suryanarayanan A, Carter J M, Landin J D, Morrow A L, Werner D F, Spigelman I
Department of Pharmaceutical Sciences, University of the Sciences, Philadelphia College of Pharmacy, Philadelphia, PA 19104, USA.
Department of Psychology, Center for Development and Behavioral Neuroscience, Binghamton University, Binghamton, NY 13902, USA.
Neuropharmacology. 2016 Aug;107:181-188. doi: 10.1016/j.neuropharm.2016.03.027. Epub 2016 Mar 22.
Mounting evidence indicates that ethanol (EtOH) exposure activates neuroimmune signaling. Alterations in pro-inflammatory cytokines after acute and chronic EtOH exposure have been heavily investigated. In contrast, little is known about the regulation of neurotransmission and/or modulation by anti-inflammatory cytokines in the brain after an acute EtOH exposure. Recent evidence suggests that interleukin-10 (IL-10), an anti-inflammatory cytokine, is upregulated during withdrawal from chronic EtOH exposure. In the present study, we show that IL-10 is increased early (1 h) after a single intoxicating dose of EtOH (5 g/kg, intragastric) in Sprague Dawley rats. We also show that IL-10 rapidly regulates GABAergic transmission in dentate gyrus neurons. In brain slice recordings, IL-10 application dose-dependently decreases miniature inhibitory postsynaptic current (mIPSC) area and frequency, and decreases the magnitude of the picrotoxin sensitive tonic current (Itonic), indicating both pre- and postsynaptic mechanisms. A PI3K inhibitor LY294002 (but not the negative control LY303511) ablated the inhibitory effects of IL-10 on mIPSC area and Itonic, but not on mIPSC frequency, indicating the involvement of PI3K in postsynaptic effects of IL-10 on GABAergic transmission. Lastly, we also identify a novel neurobehavioral regulation of EtOH sensitivity by IL-10, whereby IL-10 attenuates acute EtOH-induced hypnosis. These results suggest that EtOH causes an early release of IL-10 in the brain, which may contribute to neuronal hyperexcitability as well as disturbed sleep seen after binge exposure to EtOH. These results also identify IL-10 signaling as a potential therapeutic target in alcohol-use disorders and other CNS disorders where GABAergic transmission is altered.
越来越多的证据表明，乙醇（EtOH）暴露会激活神经免疫信号。急性和慢性EtOH暴露后促炎细胞因子的变化已得到大量研究。相比之下，对于急性EtOH暴露后大脑中抗炎细胞因子对神经传递的调节和/或调制作用知之甚少。最近的证据表明，白细胞介素-10（IL-10），一种抗炎细胞因子，在慢性EtOH暴露戒断期间上调。在本研究中，我们表明，在给予Sprague Dawley大鼠单次中毒剂量的EtOH（5 g/kg，胃内给药）后早期（1小时）IL-10会增加。我们还表明，IL-10能快速调节齿状回神经元中的GABA能传递。在脑片记录中，应用IL-10剂量依赖性地降低微小抑制性突触后电流（mIPSC）的面积和频率，并降低印防己毒素敏感的强直电流（Itonic）的幅度，表明存在突触前和突触后机制。PI3K抑制剂LY294002（而非阴性对照LY303511）消除了IL-10对mIPSC面积和Itonic的抑制作用，但对mIPSC频率无影响，表明PI3K参与了IL-10对GABA能传递的突触后效应。最后，我们还确定了IL-10对EtOH敏感性的一种新的神经行为调节作用，即IL-10减弱急性EtOH诱导的催眠作用。这些结果表明，EtOH会导致大脑中IL-10的早期释放，这可能导致神经元兴奋性过高以及暴饮EtOH后出现的睡眠障碍。这些结果还确定IL-10信号通路是酒精使用障碍和其他GABA能传递改变的中枢神经系统疾病的潜在治疗靶点。
