The role of VMAT-2 in mediating the impact of HIV-1 protein Tat and methamphetamine on dopamine neurotransmission and behavior

VMAT-2在介导HIV-1蛋白Tat和甲基苯丙胺对多巴胺神经传递和行为的影响中的作用

• 批准号: 10547890
• 负责人: Sarah Elizabeth Davis
• 金额: $ 3.87万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547890
• 关键词: Acute; Address; Apoptosis; Attenuated; Behavior; Chronic; Computer Models; Corpus striatum structure; Data; Development; Dopamine; Dopaminergic Agents; Drug Targeting; Event; Future; Genetic Transcription; Goals; HIV-1; HIV-associated neurocognitive disorder; Homeostasis; Impairment; In Vitro; Infection; Lead; Learning; Mediating; Methamphetamine; Modeling; Molecular; Motor Activity; Mus; Mutagenesis; Nerve Degeneration; Neurons; Periodicity; Persons; Pharmaceutical Preparations; Pharmacology; Proteins; Rattus; Research; Rodent; Role; Scanning; Signal Transduction; Synaptosomes; Testing; Therapeutic Intervention; Training; Trans-Activators; Transgenic Mice; Vesicle; Viral Load result; Work; amphetamine use; autooxidation; behavior change; behavior test; behavioral outcome; conditioned place preference; dopamine transporter; dopaminergic neuron; drug development; extracellular; in vivo; inhibitor; insight; interest; methamphetamine abuse; methamphetamine effect; monoamine; neurotoxicity; neurotransmission; psychostimulant; response; skills; stimulant abuse; targeted treatment; uptake; vesicular monoamine transporter

Project Summary Dysregulation of dopaminergic function due to the HIV-1 transactivator of transcription (Tat) protein has been implicated in the progression of HIV-1 associated neurocognitive disorders (HAND). Tat mediates increases in dopamine (DA) release and acts as a negative allosteric modulator for the dopamine transporter (DAT). In addition to DAT, previous work has identified Tat as a negative allosteric modulator for the vesicular monoamine transporter (VMAT-2). VMAT-2 functions to repackage DA into vesicles for subsequent release. Inhibition of VMAT-2 causes dysregulation of DA neurotransmission which can lead to autooxidation of DA and apoptosis. The psychostimulant methamphetamine (METH), in addition to Tat, inhibits VMAT-2 function. METH is a highly abused psychostimulant among HIV-1 infected persons. Expression of the Tat protein has been shown to potentiate METH induced neurotoxicity and behavior. Considering the respective interactions between Tat or METH and VMAT-2, we hypothesize that the Tat and METH effects on extracellular DA and behavior are mediated by VMAT-2. We will address this hypothesis by first, determining the role for VMAT-2 in mediating Tat- induced increases in DA release (Tat alone). We will use fast scan cyclic voltammetry to quantify DA release in Tat expressing mice. Specifically, we will profile the pharmacological response to a VMAT-2 inhibitor to determine whether Tat expression alters VMAT-2 function. Second, we will use two different METH administration models (acute and chronic) and profile the response to the VMAT-2 inhibitor as in the first aim. Lastly, we will determine whether a VMAT-2 specific inhibitor attenuates Tat-potentiated METH-conditioned place preference behavior. This will give insight whether VMAT-2 mediates Tat-potentiated METH behavior. The findings from this proposal will provide key insight into the molecular mechanism by which Tat increases extracellular DA and determine whether VMAT-2 is a suitable drug target for future therapeutic intervention in the treatment of METH abuse in HIV-1 infected persons. .

项目概要 HIV-1 转录反式激活蛋白 (Tat) 导致多巴胺能功能失调 与 HIV-1 相关神经认知障碍 (HAND) 的进展有关。达调解 增加多巴胺 (DA) 释放并充当多巴胺转运蛋白的负变构调节剂 （数据）。除了 DAT 之外，之前的工作已确定 Tat 是囊泡的负变构调节剂。 单胺转运蛋白（VMAT-2）。 VMAT-2 的功能是将 DA 重新包装到囊泡中以供后续释放。 抑制 VMAT-2 会导致 DA 神经传递失调，从而导致 DA 和 细胞凋亡。除了 Tat 之外，精神兴奋剂甲基苯丙胺 (METH) 也会抑制 VMAT-2 功能。冰毒 是一种在 HIV-1 感染者中被高度滥用的精神兴奋剂。 Tat 蛋白的表达已被证实 增强冰毒引起的神经毒性和行为。考虑到 Tat 或 METH 和 VMAT-2，我们假设 Tat 和 METH 对细胞外 DA 和行为的影响是 由 VMAT-2 介导。我们将首先确定 VMAT-2 在介导 Tat 中的作用来解决这一假设 诱导 DA 释放增加（仅 Tat）。我们将使用快速扫描循环伏安法来量化 DA 的释放 Tat 表达小鼠。具体来说，我们将分析 VMAT-2 抑制剂的药理学反应 确定 Tat 表达是否改变 VMAT-2 功能。其次，我们将使用两种不同的 METH 管理模型（急性和慢性）并描述对 VMAT-2 抑制剂的反应，如第一个目标所示。 最后，我们将确定 VMAT-2 特异性抑制剂是否减弱 Tat 增强的 METH 条件作用 地点偏好行为。这将有助于了解 VMAT-2 是否介导 Tat 增强的 METH 行为。这 该提案的研究结果将为了解 Tat 增加的分子机制提供重要见解 细胞外 DA 并确定 VMAT-2 是否是未来治疗干预的合适药物靶点 HIV-1 感染者滥用冰毒的治疗。 。