HIV-1 transgenic rats display an increase in [(3)H]dopamine uptake in the prefrontal cortex and striatum.
HIV-1 transgenic rats display an increase in [(3)H]dopamine uptake in the prefrontal cortex and striatum.
复制标题
HIV-1转基因大鼠的前额皮质和纹状体中[(3)H]多巴胺摄取增加。
DOI：
10.1007/s13365-015-0391-6
复制
发表时间：
2016
影响因子：
3.2
通讯作者：
Zhan,Chang-Guo
中科院分区：
文献类型：
--
作者：
Zhu,Jun;Yuan,Yaxia;Midde,NarasimhaM;Gomez,AdrianM;Sun,Wei-Lun;Quizon,PamelaM;Zhan,Chang-Guo
中枢神经系统内的HIV病毒蛋白与HIV感染个体的神经认知障碍的发展相关。多巴胺转运蛋白（DAT）介导的多巴胺转运对正常多巴胺稳态至关重要。异常多巴胺能传递被认为是HIV诱导的神经认知障碍的风险决定因素。我们已发表的工作表明，转录反式激活因子（达特）诱导的DAT抑制是由DAT上的变构结合位点介导的，而不是与多巴胺摄取位点的相互作用。本研究调查是否受损的DAT功能诱导的达特暴露在体外可以记录在HIV-1转基因（HIV-1 Tg）大鼠。我们评估了[3 H]多巴胺摄取到前额叶和纹状体突触体的HIV-1 Tg和Fisher 344大鼠的动力学分析。与Fisher 344大鼠相比，HIV-1 Tg大鼠前额叶皮层和纹状体的多巴胺转运能力分别增加了34%和32%。表面生物素化的评估表明，DAT在质膜的表达减少PFC和增强纹状体，分别为HIV-1 Tg大鼠。虽然[3 H]WIN 35，428的最大结合位点（Bmax）在HIV-1 Tg大鼠的纹状体中降低，但发现相对于Fisher 344大鼠，DAT转换比例增加。总之，这些研究结果表明，DAT功能的神经适应性变化在HIV-1 Tg大鼠中得到证实，这可能是对病毒蛋白诱导的异常多巴胺能传递的补偿。因此，我们的研究为理解neuroAIDS中明显的神经认知障碍机制提供了新的见解。
HIV viral proteins within the central nervous system are associated with the development of neurocognitive impairments in HIV-infected individuals. Dopamine transporter (DAT)-mediated dopamine transport is critical for normal dopamine homeostasis. Abnormal dopaminergic transmission has been implicated as a risk determinant of HIV-induced neurocognitive impairments. Our published work has demonstrated that transactivator of transcription (Tat)-induced inhibition of DAT is mediated by allosteric binding site(s) on DAT, not the interaction with the dopamine uptake site. The present study investigated whether impaired DAT function induced by Tat exposure in vitro can be documented in HIV-1 transgenic (HIV-1Tg) rats. We assessed kinetic analyses of [3H]dopamine uptake into prefrontal and striatal synaptosomes of HIV-1Tg and Fisher 344 rats. Compared with Fisher 344 rats, the capacity of dopamine transport in the prefrontal cortex (PFC) and striatum of HIV-1Tg rats was increased by 34 and 32 %, respectively. Assessment of surface biotinylation indicated that DAT expression in the plasma membrane was reduced in PFC and enhanced in striatum, respectively, of HIV-1Tg rats. While the maximal binding sites (Bmax) of [3H]WIN 35,428 was decreased in striatum of HIV-1Tg rats, an increase in DAT turnover proportion was found, relative to Fisher 344 rats. Together, these findings suggest that neuroadaptive changes in DAT function are evidenced in the HIV-1Tg rats, perhaps compensating for viral-protein-induced abnormal dopaminergic transmission. Thus, our study provides novel insights into understanding mechanism underlying neurocognitive impairment evident in neuroAIDS.