Role of tumor necrosis factor-α in methamphetamine-induced drug dependence and neurotoxicity
Role of tumor necrosis factor-α in methamphetamine-induced drug dependence and neurotoxicity
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DOI：
10.1523/jneurosci.4847-03.2004
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发表时间：
2004-03-03
影响因子：
5.3
通讯作者：
Nabeshima, T
中科院分区：
文献类型：
--
作者：
Nakajima, A;Yamada, K;Nabeshima, T
肿瘤坏死因子-α (TNF-α) 是一种促炎细胞因子，现已成为中枢神经系统功能的重要调节剂。甲基苯丙胺 (METH) 是一种广泛滥用的精神兴奋剂，会导致欣快感、多动症和药物依赖。高剂量的冰毒会对多巴胺能神经元造成长期神经毒性。在这项研究中，我们研究了 TNF-α 在 METH 诱导的依赖性和神经毒性中的作用。大鼠重复使用冰毒（2 mg/kg，持续 5 天）治疗可诱导大脑中 TNF-α mRNA 和蛋白质表达显着增加。外源性 TNF-α（1 - 4 杯）可阻断 METH 的运动刺激和奖励作用，以及 METH（4 mg/kg；每隔 2 小时间隔四次）诱导的小鼠多巴胺能神经毒性。为了研究内源性 TNF-α 在冰毒行为和神经化学效应中的作用，我们使用了 TNF-α 基因有针对性删除的小鼠。与野生型小鼠相比，TNF-α- (-/-) 小鼠对 METH 的运动敏化、奖励和神经毒性作用表现出增强的反应。我们还在 C57BL/6 小鼠体内和体外研究了 TNF-α 在 METH 诱导的多巴胺 (DA) 释放和摄取中的作用。外源性 TNF-α（4 杯）在体内减弱了 METH 诱导的细胞外纹状体 DA 的增加，并在体外和体内增强了突触体对纹状体 DA 的摄取。此外，TNF-α 本身可激活囊泡 DA 摄取，并减少 METH 诱导的囊泡 DA 摄取减少。我们的研究结果表明，TNF-α 通过激活质膜和囊泡 DA 转运蛋白以及抑制 METH 诱导的细胞外 DA 水平增加，在 METH 诱导的药物依赖和神经毒性中发挥神经保护作用。
Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, is now emerging as an important modulator of the function of the CNS. Methamphetamine ( METH) is a widely abused psychostimulant that causes euphoria, hyperactivity, and drug dependence. High doses of METH cause long-term neurotoxicity in dopaminergic neurons. In this study, we investigated a role of TNF-alpha in METH-induced dependence and neurotoxicity. Repeated treatment with METH (2 mg/kg for 5 d) in rats induced a significant increase in TNF-alpha mRNA and protein expression in the brain. Exogenous TNF-alpha (1 - 4 mug) blocked locomotor-stimulating and rewarding effects of METH, as well as METH (4 mg/kg; four times at 2 hr intervals)-induced dopaminergic neurotoxicity in mice. To examine a role of endogenous TNF-alpha in behavioral and neurochemical effects of METH, we used mice with targeted deletions of the TNF-alpha gene. TNF-alpha- (-/-) mice showed enhanced responses to the locomotor-sensitizing, rewarding, and neurotoxic effects of METH compared with wild-type mice. We also examined the role of TNF-alpha in METH-induced dopamine (DA) release and uptake in vitro and in vivo in C57BL/6 mice. Exogenous TNF-alpha (4 mug) attenuated the METH-induced increase in extracellular striatal DA in vivo and potentiated striatal DA uptake into synaptosomes in vitro and in vivo. Furthermore, TNF-alpha activated vesicular DA uptake by itself and diminished the METH-induced decrease in vesicular DA uptake. Our findings suggest that TNF-alpha plays a neuroprotective role in METH-induced drug dependence and neurotoxicity by activating plasmalemmal and vesicular DA transporter as well as inhibiting METH-induced increase in extracellular DA levels.