Niwa Minae, Nitta Atsumi, Cen Xiaobo, Kitaichi Kiyoyuki, Ozaki Norio, Yamada Kiyofumi, Nabeshima Toshitaka
Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
J Neurochem. 2008 Dec;107(6):1697-708. doi: 10.1111/j.1471-4159.2008.05738.x. Epub 2008 Nov 5.
The psychostimulant properties of methamphetamine (METH) are associated with an increase in extracellular dopamine (DA) levels in the brain, via facilitation of DA's release from pre-synaptic nerve terminals and inhibition of its reuptake through DA transporter. Recently, we have demonstrated that tumor necrosis factor-alpha (TNF-alpha) increases DA uptake and inhibits METH dependence. Moreover, we have clarified 'shati' identified in the nucleus accumbens of mice treated with METH is involved in METH dependence. In the present study, we investigated the effects of TNF-alpha on DA uptake in PC12 cells and established a PC12 cell line transfected with a vector containing shati cDNA to examine the precise mechanism behind the role of shati in DA uptake. Moreover, we examined the relationship between shati and TNF-alpha. TNF-alpha increased DA uptake via the mitogen-activated protein kinase kinase pathway and inhibited the METH-induced decrease in DA uptake in PC12 cells. Transfection of the vector containing shati cDNA into PC12 cells, induced the expression of shati and TNF-alpha mRNA, accelerated DA uptake, and inhibited the METH-induced decrease in DA uptake. These results suggest that the functional roles of shati in METH-regulated behavioral changes are mediated through inhibition of the METH-induced decrease in DA uptake via TNF-alpha.
甲基苯丙胺（METH）的精神刺激特性与大脑细胞外多巴胺（DA）水平的升高有关，这是通过促进DA从突触前神经末梢的释放以及抑制其通过多巴胺转运体的再摄取来实现的。最近，我们已经证明肿瘤坏死因子-α（TNF-α）会增加DA摄取并抑制METH依赖性。此外，我们已经阐明在用METH处理的小鼠伏隔核中鉴定出的“shati”与METH依赖性有关。在本研究中，我们研究了TNF-α对PC12细胞中DA摄取的影响，并建立了用含有shati cDNA的载体转染的PC12细胞系，以研究shati在DA摄取中作用背后的精确机制。此外，我们研究了shati与TNF-α之间的关系。TNF-α通过丝裂原活化蛋白激酶激酶途径增加DA摄取，并抑制METH诱导的PC12细胞中DA摄取的减少。将含有shati cDNA的载体转染到PC12细胞中，诱导了shati和TNF-α mRNA的表达，加速了DA摄取，并抑制了METH诱导的DA摄取的减少。这些结果表明，shati在METH调节的行为变化中的功能作用是通过抑制TNF-α介导的METH诱导的DA摄取减少来实现的。
