Innate immune signaling in the ventral tegmental area contributes to drug-primed reinstatement of cocaine seeking.
Innate immune signaling in the ventral tegmental area contributes to drug-primed reinstatement of cocaine seeking.
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DOI：
10.1016/j.bbi.2017.08.012
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发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
Bachtell RK
中科院分区：
文献类型：
--
作者：
Brown KT;Levis SC;O'Neill CE;Northcutt AL;Fabisiak TJ;Watkins LR;Bachtell RK
可卡因成瘾是一种慢性复发性疾病，其特征是持续扰乱机体的体内平衡过程，导致不适应药物寻求。尽管人们对长期服用可卡因后神经元变化的后果给予了相当大的关注，但很少有研究探讨长期服用可卡因后小胶质细胞的作用，小胶质细胞是大脑中常驻的免疫细胞。Toll样受体4(TLR4)是一种分子模式受体，识别病原体、危险信号和外源物质，并在中枢神经系统中诱导促炎信号。TLR4通常被认为主要由小胶质细胞表达。在这里，我们使用了一个可卡因成瘾的啮齿动物模型来研究腹侧被盖区(VTA)中TLR4在寻找可卡因过程中的作用。雄性SD大鼠在每天2小时的训练中自我给予可卡因，持续15天。在自我给药后，大鼠接受了灭绝训练，并在药物启动的恢复范式中进行了测试。用球形红细菌脂多糖(LPS-RS)拮抗VTA中TLR4的药理作用可显著降低可卡因诱导的找药恢复，但对蔗糖寻找无明显影响。使用TLR4激活剂脂多糖在VTA内激活TLR4足以适度恢复可卡因寻找。我们还评估了自身注射可卡因后VTA中促炎细胞因子表达的变化。可卡因自身给药增加了促炎症细胞因子IL-1？的mRNA在VTA中的表达，但不能增加肿瘤坏死因子α的表达。VTA中白介素1受体的药理拮抗作用减少了可卡因诱导的药物寻找。这些结果与慢性可卡因产生炎症信号促进可卡因寻求的假设是一致的。
Cocaine addiction is a chronic relapsing disorder characterized by persistent perturbations to an organism’s homeostatic processes that result in maladaptive drug seeking. Although considerable attention has been directed at the consequences of neuronal changes following chronic cocaine taking, few studies have examined the role of microglia, the brain’s resident immune cells, following chronic cocaine administration. Toll-Like Receptor 4 (TLR4) is a molecular pattern receptor that recognizes pathogens, danger signals, and xenobiotics and induces proinflammatory signaling in the central nervous system. TLR4 is generally considered to be expressed primarily by microglia. Here, we used a rodent model of cocaine addiction to investigate the role of TLR4 in the ventral tegmental area (VTA) in cocaine seeking. Male Sprague-Dawley rats were trained to self-administer cocaine in daily 2-h sessions for 15 days. Following self-administration, rats underwent extinction training and were tested in a drug-primed reinstatement paradigm. Pharmacological antagonism of TLR4 in the VTA using lipopolysaccharide from the bacterium Rhodobacter sphaeroides (LPS-RS) significantly reduced cocaine-primed reinstatement of drug seeking but had no effect on sucrose seeking. TLR4 activation within the VTA using the TLR4 activator, lipopolysaccharide, was sufficient to moderately reinstate cocaine seeking. We also assessed changes in proinflammatory cytokine expression in the VTA following cocaine self-administration. Cocaine self-administration increased the expression of mRNA for the proinflammatory cytokine interleukin-1ß, but not tumor necrosis factor alpha, in the VTA. Pharmacological antagonism of the interleukin-1 receptor in the VTA reduced cocaine-primed drug seeking. These results are consistent with the hypothesis that chronic cocaine produces inflammatory signaling that contributes to cocaine seeking.
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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：
3.7
作者：
Goshen, Inbal;Kreisel, Tirzah;Yirmiya, Raz
通讯作者：
Yirmiya, Raz
影响因子：
4.2
作者：
Charntikov, Sergios;Pittenger, Steven T.;Pendyala, Gurudutt
通讯作者：
Pendyala, Gurudutt
影响因子：
5.3
作者：
Alfonso-Loeches, Silvia;Pascual-Lucas, Maya;Guerri, Consuelo
通讯作者：
Guerri, Consuelo
DOI：
10.1016/b978-0-12-420118-7.00001-9
发表时间：
2014
期刊：
Advances in pharmacology (San Diego, Calif.)
影响因子：
--
作者：
Beardsley, Patrick M;Hauser, Kurt F
通讯作者：
Hauser, Kurt F