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. .

项目摘要 HIV-1转录剂（TAT）蛋白的多巴胺能功能失调 与HIV-1相关的神经认知障碍的进展有关（手）。 tat介导 多巴胺（DA）释放的增加并充当多巴胺转运蛋白的负变构调节剂 （dat）。除了DAT之外，先前的工作还确定了TAT是囊泡的负变构调节器 单胺转运蛋白（VMAT-2）。 VMAT-2功能将DA重新包装到囊泡中以进行后续释放。 抑制VMAT-2会导致DA神经传递失调，从而导致DA和 凋亡。除TAT外，精神刺激性甲基苯丙胺（METH）抑制了VMAT-2功能。冰毒 是HIV-1感染者中高度虐待的心理刺激。已经显示了TAT蛋白的表达 增强甲基苯甲酸甲酯诱导的神经毒性和行为。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。我们将首先通过首先解决这一假设，确定VMAT-2在介导Tat-中的作用 DA释放的诱导增加（单独使用TAT）。我们将使用快速扫描循环伏安法来量化DA释放 表达小鼠的tat。具体而言，我们将对VMAT-2抑制剂的药理反应介绍 确定TAT表达是否会改变VMAT-2功能。其次，我们将使用两种不同的甲基苯丙胺 行政模型（急性和慢性）以及对VMAT-2抑制剂的反应如第一个目标。 最后，我们将确定VMAT-2特异性抑制剂是否会减弱TAT功能赋予的甲基化条件 放置偏好行为。这将使VMAT-2是否介导TAT启用的METH行为。这 该提案的发现将为TAT增加的分子机制提供关键的见解 细胞外DA并确定VMAT-2是否是未来治疗干预的合适药物靶标 在HIV-1感染的人中滥用甲基苯丙胺的治疗。 。