Experimental Traumatic Brain Injury Alters Ethanol Consumption and Sensitivity
Experimental Traumatic Brain Injury Alters Ethanol Consumption and Sensitivity
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DOI：
10.1089/neu.2013.3286
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发表时间：
2014-10-15
影响因子：
4.2
通讯作者：
Conti, Alana C.
中科院分区：
文献类型：
--
作者：
Lowing, Jennifer L.;Susick, Laura L.;Conti, Alana C.
外伤性脑损伤（TBI）后酒精消费模式的改变可导致TBI恢复的显著损伤。很少有临床前模型用于检查损伤后不同阶段的酒精使用情况，导致机制问题没有得到解答。为了解决这个问题，本研究的目的是描述小鼠非挫伤闭头脑外伤的组织学和行为结果，之后对酒精的敏感性和消耗进行量化，以及多巴胺能信号标记。我们假设脑外伤会改变酒精消费模式和相关的信号转导途径，这与临床观察一致。对C57BL/6J小鼠颅骨中线撞击后、损伤后向右潜伏期、运动缺陷、外伤性轴索损伤和反应性星形胶质细胞增生进行了评估。在脑损伤后6、24和72 h，在白质束中观察到淀粉样前体蛋白（APP）的积累。脑外伤后24小时内观察到胶质原纤维酸性蛋白（GFAP）免疫反应性增强，主要发生在撞击部位和纹状体亚区伏隔核，最早出现在72小时，持续至7天。在tbi后14天，当小鼠在急性高剂量乙醇（4 g/kg，腹腔注射）后进行乙醇敏感性测试时，脑损伤小鼠比未损伤小鼠镇静时间增加，并伴有纹状体多巴胺和camp调节的神经元磷酸化蛋白32 kDa （DARPP-32）磷酸化的缺陷。在脑外伤后17天，使用黑暗中饮酒范式评估乙醇摄入量。与假对照组相比，TBI小鼠在7天内的饮酒量显著减少，与临床观察到的损伤后最初阶段酒精摄入量的减少相似。这些数据表明，创伤性脑损伤增加了对乙醇诱导的镇静的敏感性，并在改变乙醇消耗的同时影响纹状体多巴胺能神经传递的下游信号介质。检查脑外伤对乙醇反应的影响将提高我们对脑外伤后人类酒精使用的理解。
Altered alcohol consumption patterns after traumatic brain injury (TBI) can lead to significant impairments in TBI recovery. Few preclinical models have been used to examine alcohol use across distinct phases of the post-injury period, leaving mechanistic questions unanswered. To address this, the aim of this study was to describe the histological and behavioral outcomes of a noncontusive closed-head TBI in the mouse, after which sensitivity to and consumption of alcohol were quantified, in addition to dopaminergic signaling markers. We hypothesized that TBI would alter alcohol consumption patterns and related signal transduction pathways that were congruent to clinical observations. After midline impact to the skull, latency to right after injury, motor deficits, traumatic axonal injury, and reactive astrogliosis were evaluated in C57BL/6J mice. Amyloid precursor protein (APP) accumulation was observed in white matter tracts at 6, 24, and 72 h post-TBI. Increased intensity of glial fibrillary acidic protein (GFAP) immunoreactivity was observed by 24 h, primarily under the impact site and in the nucleus accumbens, a striatal subregion, as early as 72 h, persisting to 7 days, after TBI. At 14 days post-TBI, when mice were tested for ethanol sensitivity after acute high-dose ethanol (4 g/kg, intraperitoneally), brain-injured mice exhibited increased sedation time compared with uninjured mice, which was accompanied by deficits in striatal dopamine-and cAMP-regulated neuronal phosphoprotein, 32 kDa (DARPP-32) phosphorylation. At 17 days post-TBI, ethanol intake was assessed using the Drinking-in-the-Dark paradigm. Intake across 7 days of consumption was significantly reduced in TBI mice compared with sham controls, paralleling the reduction in alcohol consumption observed clinically in the initial post-injury period. These data demonstrate that TBI increases sensitivity to ethanol-induced sedation and affects downstream signaling mediators of striatal dopaminergic neurotransmission while altering ethanol consumption. Examining TBI effects on ethanol responsitivity will improve our understanding of alcohol use post-TBI in humans.