Involvement of the accumbal osteopontin-interacting transmembrane protein 168 in methamphetamine-induced place preference and hyperlocomotion in mice.
Involvement of the accumbal osteopontin-interacting transmembrane protein 168 in methamphetamine-induced place preference and hyperlocomotion in mice.
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DOI：
10.1038/s41598-017-13289-0
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发表时间：
2017-10-12
影响因子：
4.6
通讯作者：
Nitta A
中科院分区：
文献类型：
--
作者：
Fu K;Miyamoto Y;Otake K;Sumi K;Saika E;Matsumura S;Sato N;Ueno Y;Seo S;Uno K;Muramatsu SI;Nitta A
长期接触甲基苯丙胺会导致大脑的适应性变化，这是依赖症状的基础。我们已经发现，跨膜蛋白168（TMEM 168）在重复甲基苯丙胺给药后，在小鼠的丘脑核中过表达。在此，我们首次证明了TMEM 168对甲基苯丙胺诱导的小鼠行为变化的抑制作用，并试图阐明这种抑制作用的机制。我们通过使用腺相关病毒载体（NAc-TMEM小鼠）在小鼠的延髓核中过表达TMEM 168。甲基苯丙胺诱导的过度运动和条件性位置偏爱在NAc-TMEM小鼠中减弱。此外，甲基苯丙胺诱导的细胞外多巴胺升高在NAc-TMEM小鼠的延髓核中被抑制。接下来，我们通过在培养的COS-7细胞中进行免疫沉淀，鉴定了细胞外基质蛋白骨桥蛋白作为TMEM 168的相互作用伴侣。TMEM 168在COS-7细胞中的过表达诱导细胞外和细胞内骨桥蛋白的增强。类似地，在体内研究中，在NAc-TMEM小鼠的髓核中也观察到骨桥蛋白增强。此外，注入骨桥蛋白到小鼠延髓核被发现抑制甲基苯丙胺诱导的过度运动和条件性位置偏爱。我们的研究表明，TMEM 168调控的骨桥蛋白系统是一种新的治疗甲基苯丙胺依赖的靶向途径，通过调节多巴胺能神经元的功能。
Chronic exposure to methamphetamine causes adaptive changes in brain, which underlie dependence symptoms. We have found that the transmembrane protein 168 (TMEM168) is overexpressed in the nucleus accumbens of mice upon repeated methamphetamine administration. Here, we firstly demonstrate the inhibitory effect of TMEM168 on methamphetamine-induced behavioral changes in mice, and attempt to elucidate the mechanism of this inhibition. We overexpressed TMEM168 in the nucleus accumbens of mice by using an adeno-associated virus vector (NAc-TMEM mice). Methamphetamine-induced hyperlocomotion and conditioned place preference were attenuated in NAc-TMEM mice. Additionally, methamphetamine-induced extracellular dopamine elevation was suppressed in the nucleus accumbens of NAc-TMEM mice. Next, we identified extracellular matrix protein osteopontin as an interacting partner of TMEM168, by conducting immunoprecipitation in cultured COS-7 cells. TMEM168 overexpression in COS-7 cells induced the enhancement of extracellular and intracellular osteopontin. Similarly, osteopontin enhancement was also observed in the nucleus accumbens of NAc-TMEM mice, in in vivo studies. Furthermore, the infusion of osteopontin proteins into the nucleus accumbens of mice was found to inhibit methamphetamine-induced hyperlocomotion and conditioned place preference. Our studies suggest that the TMEM168-regulated osteopontin system is a novel target pathway for the therapy of methamphetamine dependence, via regulating the dopaminergic function in the nucleus accumbens.
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影响因子：
6.2
作者：
Grant, Kathleen M.;LeVan, Tricia D.;Wells, Sandra M.;Li, Ming;Stoltenberg, Scott F.;Gendelman, Howard E.;Carlo, Gustavo;Bevins, Rick A.
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影响因子：
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