Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4.
Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4.
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DOI：
10.2174/1871527314666150529132503
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Watkins LR
中科院分区：
文献类型：
--
作者：
Bachtell R;Hutchinson MR;Wang X;Rice KC;Maier SF;Watkins LR
越来越多的人认识到，神经胶质促炎活性对包括可卡因、甲基苯丙胺、阿片类药物和酒精在内的各种滥用药物的奖赏和增强作用具有重要作用。最近有人提出，胶质细胞正在识别并被这样的药物激活，比如对这些物质是异物的中枢神经系统免疫反应；也就是说，大脑中的外来物质。各种滥用药物通过Toll样受体4(TLR4)激活神经胶质细胞，主要是小胶质细胞。TLR4检测到这类异物会导致神经胶质兴奋性物质和神经毒性物质的释放。这些TLR4激活的胶质产物增强了大脑奖励回路中神经元的兴奋性，从而增强了它们的奖励和强化效应。事实上，对TLR4激活的选择性药理阻断，如非阿片类TLR4拮抗剂(+)-纳曲酮，抑制了药物奖励/强化的一些指数。这些包括：条件性位置偏爱，自我给药，药物诱导的恢复，对欲望的孵化，以及伏隔核壳多巴胺的升高。值得注意的是，TLR4的封锁未能改变食物的自我给药，这表明了对滥用药物的选择性影响。TLR4信号的遗传破坏概括了药物阻断TLR4的效果，为TLR4的核心重要性提供了一致的证据。综上所述，多条证据汇聚在一起，将TLR4提升为有希望的药物滥用治疗靶点。
There is growing recognition that glial proinflammatory activation importantly contributes to the rewarding and reinforcing effects of a variety of drugs of abuse, including cocaine, methamphetamine, opioids, and alcohol. It has recently been proposed that glia are recognizing, and becoming activated by, such drugs as a CNS immunological response to these agents being xenobiotics; that is, substances foreign to the brain. Activation of glia, primarily microglia, by various drugs of abuse occurs via toll like receptor 4 (TLR4). The detection of such xenobiotics by TLR4 results in the release of glial neuroexcitatory and neurotoxic substances. These glial products of TLR4 activation enhance neuronal excitability within brain reward circuitry, thereby enhancing their rewarding and reinforcing effects. Indeed, selective pharmacological blockade of TLR4 activation, such as with the non-opioid TLR4 antagonist (+)-naltrexone, suppresses a number of indices of drug reward/reinforcement. These include: conditioned place preference, self-administration, drug-primed reinstatement, incubation of craving, and elevations of nucleus accumbens shell dopamine. Notably, TLR4 blockade fails to alter self-administration of food, indicative of a selective effect on drugs of abuse. Genetic disruption of TLR4 signaling recapitulates the effects of pharmacological TLR4 blockade, providing converging lines of evidence of a central importance of TLR4. Taken together, multiple lines of evidence converge to raise TLR4 as a promising therapeutic target for drug abuse.
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影响因子：
11
作者：
Fairbanks, CA;Wilcox, GL
通讯作者：
Wilcox, GL
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.
影响因子：
5.3
作者：
Alfonso-Loeches, Silvia;Pascual-Lucas, Maya;Guerri, Consuelo
通讯作者：
Guerri, Consuelo
影响因子：
2.7
作者：
Li, XC;Karadsheh, MS;Stitzel, JA
通讯作者：
Stitzel, JA
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.