A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression.
A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression.
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前额皮质 NMDA 受体在小鼠酒精增强攻击性中的作用。
DOI：
10.1038/npp.2017.253
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Miczek,KlausA
中科院分区：
文献类型：
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作者：
Newman,EmilyL;Terunuma,Miho;Wang,TiffanyL;Hewage,Nishani;Bicakci,MatthewB;Moss,StephenJ;DeBold,JosephF;Miczek,KlausA
在美国，酒精与近一半的暴力犯罪有关;然而，这种病理性攻击的潜在神经基础仍然难以捉摸。酒精可能作用于皮层回路内的N-甲基-d-天冬氨酸受体（NMDAR），以阻碍加工并促进攻击性。在这里，雄性小鼠的特点是酒精升高（AHA）或酒精非升高的侵略者（ANA）在居民入侵者的对抗后，自我管理1.0克/公斤的酒精（6% w/v）或水。酒精在AHAs中产生了一种病理性的攻击模式;这些小鼠将它们的叮咬转移到顺从动物身体上更脆弱的位置，包括饮酒后的前背部和腹部。此外，通过免疫印迹，我们发现，AHAs过度表达NMDAR GluN 2D亚基在前额叶皮层（PFC）相比，ANA，而两种表型表达相似水平的GluN 1，GluN 2A和GluN 2B。在确定了区分AHA和ANA的几个行为和分子特征后，我们测试了额外的小鼠在含有GluN 2D的NMDAR的优先拮抗作用后的攻击性。在这些实验中，AHA和ANA组在接受腹膜内（ip）剂量的氯胺酮或美金刚胺或将美金刚胺直接输注到前边缘（PLmPFC）或下边缘内侧PFC（ILmPFC）之前自我施用1.0 g/kg酒精（6% w/v）或水。中等剂量的IP氯胺酮、IP美金刚或PLmPFC内美金刚增加了AHA的攻击性，但仅在不存在酒精的情况下。先前的酒精摄入阻断了氯胺酮或美金刚胺的亲攻击作用。相比之下，只有美金刚，管理系统或内PLmPFC，与先前的酒精摄入量的互动，以升级侵略ANA。ILmPFC内美金刚胺对AHA或ANA的攻击性没有影响。总之，这项工作说明了含GluN 2D的NMDARs在PLmPFC中在酒精增强的攻击中的潜在作用。含GluN 2D的NMDAR在含小白蛋白的皮质中间神经元上高度表达，这表明在一部分个体中，酒精可能在功能上改变皮质微电路内的信号整合，以失调威胁反应并促进攻击。这项工作表明，针对GluN 2D-NMDAR可能有助于减少与酒精相关的暴力对人类的影响。
Alcohol is associated with nearly half of all violent crimes committed in the United States; yet, a potential neural basis for this type of pathological aggression remains elusive. Alcohol may act on N-methyl-d-aspartate receptors (NMDARs) within cortical circuits to impede processing and to promote aggression. Here, male mice were characterized as alcohol-heightened (AHAs) or alcohol non-heightened aggressors (ANAs) during resident–intruder confrontations after self-administering 1.0 g/kg alcohol (6% w/v) or water. Alcohol produced a pathological-like pattern of aggression in AHAs; these mice shifted their bites to more vulnerable locations on the body of a submissive animal, including the anterior back and ventrum after consuming alcohol. In addition, through immunoblotting, we found that AHAs overexpressed the NMDAR GluN2D subunit in the prefrontal cortex (PFC) as compared to ANAs while the two phenotypes expressed similar levels of GluN1, GluN2A and GluN2B. After identifying several behavioral and molecular characteristics that distinguish AHAs from ANAs, we tested additional mice for their aggression following preferential antagonism of GluN2D-containing NMDARs. In these experiments, groups of AHAs and ANAs self-administered 1.0 g/kg alcohol (6% w/v) or water before receiving intraperitoneal (ip) doses of ketamine or memantine, or infusions of memantine directly into the prelimbic (PLmPFC) or infralimbic medial PFC (ILmPFC). Moderate doses of IP ketamine, IP memantine, or intra-PLmPFC memantine increased aggression in AHAs, but only in the absence of alcohol. Prior alcohol intake blocked the pro-aggressive effects of ketamine or memantine. In contrast, only memantine, administered systemically or intra-PLmPFC, interacted with prior alcohol intake to escalate aggression in ANAs. Intra-ILmPFC memantine had no effect on aggression in either AHAs or ANAs. In sum, this work illustrates a potential role of GluN2D-containing NMDARs in the PLmPFC in alcohol-heightened aggression. GluN2D-containing NMDARs are highly expressed on cortical parvalbumin-containing interneurons, suggesting that, in a subset of individuals, alcohol may functionally alter signal integration within cortical microcircuits to dysregulate threat reactivity and promote aggression. This work suggests that targeting GluN2D-NMDARs may be of use in reducing the impact of alcohol-related violence in the human population.