Induction of innate immune genes in brain create the neurobiology of addiction.
Induction of innate immune genes in brain create the neurobiology of addiction.
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DOI：
10.1016/j.bbi.2011.03.003
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发表时间：
2011-06
影响因子：
15.1
通讯作者：
Qin, Liya
中科院分区：
文献类型：
--
作者：
Crews, F. T.;Zou, Jian;Qin, Liya
关键词：
成瘾是通过反复滥用药物而发生的，这些药物逐渐降低了行为控制和认知灵活性，同时增加了边缘系统的负面情绪。最近的发现表明神经免疫信号是成瘾和共病抑郁症的基础。低阈值小胶质细胞经历先天免疫激活的进行性阶段，涉及星形胶质细胞和神经元，具有重复的药物滥用、应激和/或细胞损伤信号。促炎趋化因子、细胞因子、氧化酶、蛋白酶、TLR和其他基因的脑NF-κB转录增加产生放大NF-κB转录和先天免疫靶基因表达的环。人死后酒精性脑组织中NF-κB和NF-κB靶基因信息增加，小胶质细胞标志物和趋化因子MCP 1增加。人类NF-κB1和其他先天免疫基因的多态性与酒精中毒的遗传风险有关动物转基因和遗传研究将NF-κB先天免疫基因表达与饮酒联系起来。人类药物成瘾者表现出行为灵活性的缺陷，使用逆转学习进行临床前建模。酗酒、慢性可卡因和病变将成瘾神经生物学与额叶皮质、神经免疫信号传导和行为灵活性丧失联系起来。成瘾还涉及增加边缘系统负面情绪和抑郁样行为，这反映在海马神经发生中。先天免疫激活与神经发生的丧失和抑郁样行为的增加平行。通过抗氧化剂、抗炎剂、抗氧化剂、阿片拮抗剂和酒精依赖戒断来防止神经发生的丧失和负面影响，将边缘系统影响与先天免疫信号传导的变化联系起来。先天免疫基因诱导是成瘾和情感障碍的基础的假说为治疗创造了新的靶点。
Addiction occurs through repeated abuse of drugs that progressively reduce behavioral control and cognitive flexibility while increasing limbic negative emotion. Recent discoveries indicate neuroimmune signaling underlies addiction and co-morbid depression. Low threshold microglia undergo progressive stages of innate immune activation involving astrocytes and neurons with repeated drug abuse, stress, and/or cell damage signals. Increased brain NF-κB transcription of proinflammatory chemokines, cytokines, oxidases, proteases, TLR and other genes create loops amplifying NF-κB transcription and innate immune target gene expression. Human post-mortem alcoholic brain has increased NF-κB and NF-κB target gene message, increased microglial markers and chemokine-MCP1. Polymorphisms of human NF-κB1 and other innate immune genes contribute to genetic risk for alcoholism. Animal transgenic and genetic studies link NF-κB innate immune gene expression to alcohol drinking. Human drug addicts show deficits in behavioral flexibility modeled pre-clinically using reversal learning. Binge alcohol, chronic cocaine, and lesions link addiction neurobiology to frontal cortex, neuroimmune signaling and loss of behavioral flexibility. Addiction also involves increasing limbic negative emotion and depression-like behavior that is reflected in hippocampal neurogenesis. Innate immune activation parallels loss of neurogenesis and increased depression-like behavior. Protection against loss of neurogenesis and negative affect by anti-oxidant, anti-inflammatory, anti-depressant, opiate antagonist and abstinence from ethanol dependence link limbic affect to changes in innate immune signaling. The hypothesis that innate immune gene induction underlies addiction and affective disorders creates new targets for therapy.
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