Interaction of HIV-1 Nef and glutamate homeostasis in the nucleus accumbens during cocaine addiction

可卡因成瘾期间伏隔核中 HIV-1 Nef 和谷氨酸稳态的相互作用

• 批准号: 10763810
• 负责人: Jessalyn Gabrielle Pla Tenorio
• 金额: $ 3.86万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10763810
• 关键词: Acceleration; Acquired Immunodeficiency Syndrome; Address; Astrocytes; Behavior; Behavioral Model; Brain; Central Nervous System; Chronic; Cocaine; Cocaine Dependence; Cocaine Users; Cocaine withdrawal; Consumption; Corpus striatum structure; Cysteine; Cystine; Data; Development; Disease Progression; Down-Regulation; Drug Addiction; Drug usage; Electrophysiology (science); Equilibrium; Extinction; Glial Fibrillary Acidic Protein; Glutamate Transporter; Glutamates; HIV; HIV Infections; HIV diagnosis; HIV-1; HIV-associated neurocognitive disorder; Health; Homeostasis; Human; Illicit Drugs; Infection; Inflammation; Injecting drug user; Invaded; Knowledge; Longevity; Measurable; Measures; Mediating; Mission; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; National Institute of Drug Abuse; Nerve Degeneration; Neuroglia; Neurons; Neuropathogenesis; Neurotoxins; Neurotransmitters; Nucleus Accumbens; Pathology; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Play; Primary Cell Cultures; Production; Proteins; Public Health; Rattus; Receptor Activation; Recreation; Research; Rewards; Risk; Risk Factors; Role; Science; Self Administration; Sex Behavior; Slice; Sprague-Dawley Rats; Structure; Substance Use Disorder; Synaptic Transmission; United States; United States National Institutes of Health; Viral; Viral Load result; Viral Proteins; Virus Replication; Work; acquired factor; addiction; antiretroviral therapy; beta catenin; brain tissue; cell type; cocaine exposure; cocaine seeking; cocaine self-administration; cocaine use; comorbidity; drug seeking behavior; extracellular; high risk behavior; illicit drug use; improved; in vivo; innovation; insight; nef Protein; neuroinflammation; neurophysiology; neurotoxic; neurotoxicity; neurotransmission; new therapeutic target; novel; novel therapeutics; prevent; protein function; transmission process

Summary The recreational use of cocaine can lead to an addiction that increases the risk of acquiring the human immunodeficiency virus (HIV) through high-risk behaviors such as an increase in unprotected sexual activity, and a more rapid progression to AIDS. Approximately 33% of the 1.2 million people in the United States (US) living with HIV use illicit substances, and approximately 1 in 10 new HIV diagnoses are attributed to injection drug users every year. People living with HIV who take combination antiretroviral therapy (cART) and maintain viral loads below detectable levels live a near-normal lifespan. However, despite the advances in efficacious medication, there are still no medications that prevent the viral invasion to the central nervous system (CNS) solidifying that the risk of developing HIV-1 associated neurocognitive disorders (HAND) has not decreased. Therefore, to protect chronically infected people from the ravages of HIV-1 infection in the brain, particularly when combined with substance use disorder (SUD), it is necessary to advance the understanding of the intersection of HIV-1 and addiction to identify novel therapeutic targets. Both cocaine and HIV proteins contribute to neuronal damage during disease progression through dysregulation of glutamate homeostasis in the brain. It has been documented that as high as 19% of astrocytes in the brains of patients with severe HAND are infected with HIV-1. Nef is one of the earliest expressed viral proteins in approximately 1% of infected astrocytes. Even without measurable viral replication, Nef could contribute to continued neuronal degeneration even in patients on cART. Extracellular glutamate is normally taken up by astrocytes through a glutamate transporter (GLT-1) and exchanged for cysteine through the cystine/glutamate exchanger. β -catenin, a dual function protein, regulates the expression of glutamate transporters preventing neurotoxicity caused by excess NMDA receptor activation in neurons. However, cocaine downregulates GLT-1 and the cystine/glutamate exchanger. During withdrawal of cocaine exposure, the AMPA/NMDA ratio increases in the nucleus accumbens (NAc). The NAc is an important brain structure involved in the development of cocaine addiction. The overall objective is to study the interaction between HIV-1 Nef and cocaine related to glutamate homeostasis and drug-seeking behavior. The central hypothesis is that combined cocaine exposure and astrocytic Nef expression will exacerbate glutamate excitation inducing neurophysiological changes that strengthen synaptic transmission and reinforce the cocaine-seeking behavior. To address this hypothesis, the team will develop the following two Specific Aims. Aim 1: Determine the impact of HIV-1 Nef and cocaine on glutamatergic neurotransmission. Aim 2: Determine the impact of HIV-1 Nef on cocaine-seeking behavior in rats. With the combination of in vivo self-administration, electrophysiology, and molecular studies using brain tissue, the team will elucidate the role of HIV-1 Nef on cocaine-seeking and consumption essential to developing new therapies to treat people with HIV and SUD.

概括 可卡因的娱乐使用可以导致成瘾，从而增加获得人类的风险 免疫缺陷病毒（HIV）通过高风险行为，例如不受保护的性活动的增加， 并更快地向艾滋病发展。在美国的120万人中，约有33％（美国） 与艾滋病毒一起使用非法物质，大约有十分之一的新艾滋病毒诊断归因于注射 吸毒者每年。患有艾滋病毒的人接受抗逆转录病毒疗法并维持 低于可检测水平的病毒载荷寿命接近正常的寿命。但是，尽管有效取得了进步 药物治疗，仍然没有药物可以防止病毒入侵中枢神经系统（CNS） 巩固发展HIV-1相关的神经认知障碍（手）的风险尚未得到改善。 因此，为了保护长期感染的人免受大脑中HIV-1感染的破坏，特别是 当与药物使用障碍（SUD）结合使用时，有必要提高对人的理解 HIV-1和成瘾的交集以识别新的治疗靶标。 可卡因和艾滋病毒蛋白在疾病进展过程中通过 大脑中谷氨酸稳态的失调。已经有记录在星形胶质细胞中高达19％ 在严重手的患者的大脑中，HIV-1感染了HIV-1。 NEF是最早表达的病毒之一 大约1％的感染星形胶质细胞中的蛋白质。即使没有可测量的病毒复制，NEF也可以 即使在购物车患者中，即使在持续的神经元变性中也有贡献。细胞外谷氨酸通常为 通过星形胶质细胞通过谷氨酸转运蛋白（GLT-1）接收，并通过 胱氨酸/谷氨酸交换器。双重功能蛋白的β-蛋白质调节谷氨酸的表达 由神经元中过量的NMDA受体激活引起的神经毒性的转运蛋白。但是，可卡因 下调GLT-1和胱氨酸/谷氨酸交换器。在撤离可卡因暴露期间 AMPA/NMDA比增加了伏隔核（NAC）。 NAC是重要的大脑结构 在可卡因成瘾的发展中。总体目的是研究HIV-1 NEF与 可卡因与谷氨酸稳态和寻求药物的行为有关。中心假设是结合 可卡因暴露和星形胶质细胞NEF表达会加剧谷氨酸兴奋性诱导 神经生理学的变化，增强突触传播并加强可卡因寻求可卡因的行为。 为了解决这一假设，团队将开发以下两个具体目标。目标1：确定影响 HIV-1 NEF和可卡因在谷氨酸能神经传递上。目标2：确定HIV-1 NEF对 大鼠可卡因的行为。与体内自我给药，电生理学和 使用脑组织的分子研究，该团队将阐明HIV-1 NEF在寻求可卡因和寻求可卡因和 消费对于开发新疗法以治疗艾滋病毒和SUD患者。