Methamphetamine Activates Toll-Like Receptor 4 to Induce Central Immune Signaling within the Ventral Tegmental Area and Contributes to Extracellular Dopamine Increase in the Nucleus Accumbens Shell.
Methamphetamine Activates Toll-Like Receptor 4 to Induce Central Immune Signaling within the Ventral Tegmental Area and Contributes to Extracellular Dopamine Increase in the Nucleus Accumbens Shell.
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甲基苯丙胺激活 Toll 样受体 4，诱导腹侧被盖区内的中枢免疫信号传导，并有助于伏核壳中细胞外多巴胺的增加
DOI：
10.1021/acschemneuro.9b00225
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发表时间：
2019-08-21
影响因子：
5
通讯作者：
Watkins LR
中科院分区：
文献类型：
--
作者：
Wang X;Northcutt AL;Cochran TA;Zhang X;Fabisiak TJ;Haas ME;Amat J;Li H;Rice KC;Maier SF;Bachtell RK;Hutchinson MR;Watkins LR
甲基苯丙胺（冰毒）是一种全球滥用、极易上瘾的兴奋剂。虽然对甲基苯丙胺的奖励和激励效应的研究主要集中在神经元行为上，但越来越多的证据表明，甲基苯丙胺也可以靶向中枢神经系统的先天免疫细胞小胶质细胞，引起促炎介质的释放，从而放大甲基苯丙胺诱导的神经元活动的奖励变化。然而，甲基安非他明如何诱导中枢神经系统（CNS）的神经炎症反应尚不清楚。在此，我们提供了直接证据，证明甲基安非他明至少部分通过激活先天免疫toll样受体4 （TLR4）产生神经炎症。生物物理研究表明，甲基安非他明与TLR4的关键共受体MD-2结合。分子动力学模拟表明，甲基甲氧基结合稳定了活性异四聚体（TLR4/MD-2）2构象。经典TLR4拮抗剂LPS-RS和TAK-242减弱甲基安非他明诱导的小胶质细胞NF-κB活化，而添加MD-2蛋白则增强甲基安非他明诱导的NF-κB活化。系统管理冰毒(1毫克/公斤)被发现对具体调控表达的CD11b(小胶质激活标记)和促炎细胞因子白介素6 (il - 6) mrna在腹侧被盖区(VTA),但不是在伏隔核壳(NAc)或前额叶皮层(PFC)。全身给予非阿片类、可透过血脑屏障的TLR4拮抗剂(+)-纳洛酮可抑制甲基苯丙胺诱导的小胶质细胞活化和VTA中IL-6 mRNA的过表达。研究发现，甲基安非他明增加了NAc中条件位置偏好（CPP）和细胞外多巴胺浓度，而这两种作用都被非阿片类TLR4拮抗剂(+)-纳洛酮抑制。此外，在vta内注射LPS-RS或IL-6中和抗体可抑制meth诱导的细胞外NAc多巴胺升高。综上所述，这一系列研究表明，冰毒诱导的神经炎症至少部分是由VTA内的TLR4-IL6信号介导的，该信号具有升高NAc壳中多巴胺的下游作用。这些结果为急性甲基苯丙胺奖赏的神经生物学机制提供了新的理解，其中包括中枢免疫信号的关键作用，并为治疗药物滥用的药物开发提供了新的靶点。
Methamphetamine (METH) is a globally abused, highly addictive stimulant. While investigations of the rewarding and motivational effects of METH have focused on neuronal actions, increasing evidence suggests that METH can also target microglia, the innate immune cells of the central nervous system, causing release of proinflammatory mediators and therefore amplifying the reward changes in the neuronal activity induced by METH. However, how METH induces neuroinflammatory responses within the central nervous system (CNS) is unknown. Herein, we provide direct evidence that METH creates neuroinflammation, at least in part, via the activation of the innate immune Toll-like receptor 4 (TLR4). Biophysical studies revealed that METH bound to MD-2, the key co-receptor of TLR4. Molecular dynamics simulations showed METH binding stabilized the active heterotetramer (TLR4/MD-2)2 conformation. Classic TLR4 antagonists LPS-RS and TAK-242 attenuated METH induced NF-κB activation of microglia, whereas added MD-2 protein boosted METH-induced NF-κB activation. Systemically administered METH (1 mg/kg) was found to specifically up-regulate expression of both CD11b (microglial activation marker) and the proinflammatory cytokine interleukin 6 (IL-6) mRNAs in the ventral tegmental area (VTA), but not in either the nucleus accumbens shell (NAc) or prefrontal cortex (PFC). Systemic administration of a non-opioid, blood-brain barrier permeable TLR4 antagonist (+)-naloxone inhibited METH-induced activation of microglia and IL-6 mRNA over-expression in VTA. METH was found to increase conditioned place preference (CPP) as well as extracellular dopamine concentrations in the NAc, with both effects suppressed by the non-opioid TLR4 antagonist (+)-naloxone. Furthermore, intra-VTA injection of LPS-RS or IL-6 neutralizing antibody suppressed METH-induced elevation of extracellular NAc dopamine. Taken together, this series of studies demonstrate that METH-induced neuroinflammation is, at least in part, mediated by TLR4-IL6 signaling within the VTA, which has the downstream effect of elevating dopamine in the NAc shell. These results provide a novel understanding of the neurobiological mechanisms underlying acute METH reward that includes a critical role for central immune signaling, and offers a new target for medication development for treating drug abuse.
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DOI：
10.1016/j.bbi.2017.08.012
发表时间：
2018-01
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Brown KT;Levis SC;O'Neill CE;Northcutt AL;Fabisiak TJ;Watkins LR;Bachtell RK
通讯作者：
Bachtell RK
影响因子：
15.1
作者：
Hutchinson, Mark R.;Zhang, Yingning;Shridhar, Mitesh;Evans, John H.;Buchanan, Madison M.;Zhao, Tina X.;Slivka, Peter F.;Coats, Benjamen D.;Rezvani, Niloofar;Wieseler, Julie;Hughes, Travis S.;Landgraf, Kyle E.;Chan, Stefanie;Fong, Stephanie;Phipps, Simon;Falke, Joseph J.;Leinwand, Leslie A.;Maier, Steven F.;Yin, Hang;Rice, Kenner C.;Watkins, Linda R.
通讯作者：
Watkins, Linda R.
Toll 样受体 4 通过星形胶质细胞中的 Caspase-11 信号通路介导甲基苯丙胺诱导的神经炎症。
影响因子：
4.8
作者：
Du SH;Qiao DF;Chen CX;Chen S;Liu C;Lin Z;Wang H;Xie WB
通讯作者：
Xie WB
影响因子：
5.3
作者：
LaVoie, MJ;Card, JP;Hastings, TG
通讯作者：
Hastings, TG
影响因子：
4
作者：
Lewis, Susannah S.;Loram, Lisa C.;Hutchinson, Mark R.;Li, Chien-Ming;Zhang, Yingning;Maier, Steven F.;Huang, Yong;Rice, Kenner C.;Watkins, Linda R.
通讯作者：
Watkins, Linda R.