Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA.
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA.
Eur J Pharmacol. 2024 Dec 5;984:177030. doi: 10.1016/j.ejphar.2024.177030. Epub 2024 Oct 2.
Perturbation of dopamine transmission has been implicated as a contributing factor in HIV-1 associated neurocognitive disorders with concurrent methamphetamine (METH) abuse. We have demonstrated that the HIV-1 protein, transactivator of transcription (Tat), decreases dopamine transport through inhibition of vesicular monoamine transporter2 (VMAT2). This study determined the effects of Tat protein on METH-inhibited VMAT2 function and METH-conditioned place preference (CPP). In vitro exposure of isolated mouse whole brain vesicles to recombinant Tat or METH displayed a concentration-dependent inhibition of the vesicular [H]Dopamine uptake, in which a combination of Tat and METH induced a greater reduction of dopamine uptake compared to Tat or METH alone. In vivo, the maximal velocity (V) of vesicular [H]Dopamine uptake was decreased in inducible Tat transgenic (iTat-tg) mice harvested after treatment with either 21-day doxycycline (Dox) or 14-day METH (3 mg/kg, i.p., daily), whereas these mice treated with both Dox and METH displayed an additive reduction of the V compared to either Tat or METH alone. Moreover, Dox-induced Tat expression increased METH-CPP in an exposure-dependent manner, with iTat-tg mice demonstrating a 2.3-fold potentiation of METH-CPP compared with Tat null control mice upon administration of Dox for 14 days. Furthermore, a 7-day administration of Dox reinstated extinguished METH-CPP. Collectively, these results suggest a synergistic effect of Tat protein and METH on inhibition of VMAT2-mediated DA transport, potentially contributing to potentiation of METH-CPP in iTat-tg mice.
多巴胺传递的扰乱被认为是 HIV-1 相关神经认知障碍的一个促成因素，同时伴有甲基苯丙胺（METH）滥用。我们已经证明，HIV-1 蛋白，转录激活物（Tat），通过抑制囊泡单胺转运体 2（VMAT2）来减少多巴胺转运。这项研究确定了 Tat 蛋白对 METH 抑制的 VMAT2 功能和 METH 条件性位置偏好（CPP）的影响。在体外，将重组 Tat 或 METH 暴露于分离的小鼠全脑囊泡中，显示出对囊泡[H]多巴胺摄取的浓度依赖性抑制，其中 Tat 和 METH 的组合比 Tat 或 METH 单独诱导更大的多巴胺摄取减少。在体内，在接受 21 天多西环素（Dox）或 14 天 METH（3mg/kg，ip，每天）治疗后收获的可诱导 Tat 转基因（iTat-tg）小鼠中，囊泡[H]多巴胺摄取的最大速度（V）降低，而这些用 Dox 和 METH 联合治疗的小鼠与单独用 Tat 或 METH 治疗的小鼠相比，V 显示出相加性降低。此外，Dox 诱导的 Tat 表达以暴露依赖性方式增加 METH-CPP，与 Tat 缺失对照小鼠相比，在给予 Dox 14 天时，iTat-tg 小鼠显示出 METH-CPP 的 2.3 倍增强。此外，7 天的 Dox 给药恢复了消退的 METH-CPP。总之，这些结果表明 Tat 蛋白和 METH 对抑制 VMAT2 介导的 DA 转运具有协同作用，可能导致 iTat-tg 小鼠中 METH-CPP 的增强。
