The human immunodeficiency virus-1-associated protein, Tat1-86, impairs dopamine transporters and interacts with cocaine to reduce nerve terminal function: a no-net-flux microdialysis study.
The human immunodeficiency virus-1-associated protein, Tat1-86, impairs dopamine transporters and interacts with cocaine to reduce nerve terminal function: a no-net-flux microdialysis study.
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DOI：
10.1016/j.neuroscience.2009.01.024
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发表时间：
2009-04-10
期刊：
影响因子：
3.3
通讯作者：
Booze, R. M.
中科院分区：
文献类型：
--
作者：
Ferris, M. J.;Frederick-Duus, D.;Fadel, J.;Mactutus, C. F.;Booze, R. M.
在美国，注射毒品约占艾滋病毒感染的三分之一。HIV相关蛋白质已被证明与各种滥用药物相互作用，以激发协同神经毒性。它们相互作用的一个共同区域是神经末梢，包括多巴胺转运蛋白（DAT）系统。然而，关于DAT功能和调节HIV感染的结果，无论药物使用，是混合的。因此，设计本实验以明确控制体内模型中的达特和可卡因施用，以调和迄今为止文献中存在的差异。我们研究了达特加可卡因诱导的变化，使用无净通量微透析，这是敏感的DAT功能的改变，以测试DAT作为HIV诱导的氧化应激和体内神经退行性变的早期介质的潜力。在5小时内的HIV相关蛋白质，达特，我们注意到一个显着的减少，在DA溢出/释放动力学的变化不大的局部DAT效率。此外，在达特给药后48小时，我们证明了HIV蛋白达特与可卡因对摄取和释放功能的协同作用。最后，我们讨论在何种程度上DAT功能障碍可能被认为是一个普遍的神经末梢功能障碍的前身。体内DAT功能障碍的表征可以提供早期药物靶标，其进而可以预防或减弱神经毒性的下游介质（即，反应性物种）对神经艾滋病中发生的DA系统的作用。
Injection drug use accounts for approximately one-third of HIV-infections in the United States. HIV associated proteins have been shown to interact with various drugs of abuse to incite concerted neurotoxicity. One common area for their interaction is the nerve terminal, including dopamine transporter (DAT) systems. However, results regarding DAT function and regulation in HIV-infection, regardless of drug use, are mixed. Thus, the present experiments were designed to explicitly control Tat and cocaine administration in an in vivo model in order to reconcile differences that exist in the literature to date. We examined Tat plus cocaine-induced alterations using no-net-flux microdialysis, which is sensitive to alterations in DAT function, in order to test the potential for DAT as an early mediator of HIV-induced oxidative stress and neurodegeneration in vivo. Within 5 hours of intra-accumbal administration of the HIV-associated protein, Tat, we noted a significant reduction in local DAT efficiency with little change in DA overflow/release dynamics. Further, at 48 hrs post-Tat administration, we demonstrated a concerted effect of the HIV-protein Tat with cocaine on both uptake and release function. Finally, we discuss the extent to which DAT dysfunction may be considered a predecessor to generalized nerve terminal dysfunction. Characterization of DAT dysfunction in vivo may provide an early pharamacotherapeutic target, which in turn may prevent or attenuate downstream mediators of neurotoxicity (i.e., reactive species) to DA systems occurring in NeuroAIDS.
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