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 娱乐性使用可卡因可能会导致成瘾，从而增加人类感染可卡因的风险 通过高危行为（例如增加无保护的性活动）感染免疫缺陷病毒（HIV）， 美国 120 万人中约有 33% 的人感染艾滋病的速度更快。 艾滋病毒感染者使用非法药物，大约十分之一的新艾滋病毒诊断归因于注射 每年都有吸毒者接受联合抗逆转录病毒治疗 (cART) 并维持治疗。 然而，尽管病毒载量低于可检测水平，但其寿命却接近正常。 药物治疗，仍然没有药物可以阻止病毒侵入中枢神经系统（CNS） 证实患 HIV-1 相关神经认知障碍 (HAND) 的风险并未降低。 因此，为了保护慢性感染者的大脑免受 HIV-1 感染的破坏，特别是 当与物质使用障碍（SUD）相结合时，有必要加深对物质使用障碍（SUD）的理解 HIV-1 和成瘾的交叉点以确定新的治疗靶点。 可卡因和 HIV 蛋白均通过以下方式在疾病进展过程中导致神经元损伤： 据记录，高达 19% 的星形胶质细胞存在大脑谷氨酸稳态失调。 严重 HAND 患者的大脑中感染了 HIV-1，Nef 是最早表达的病毒之一。 即使没有可测量的病毒复制，Nef 也可以在大约 1% 的受感染星形胶质细胞中检测到蛋白质。 即使在接受 cART 的患者中，细胞外谷氨酸通常也会导致持续的神经元变性。 通过谷氨酸转运蛋白（GLT-1）被星形胶质细胞摄取，并通过 胱氨酸/谷氨酸交换蛋白，一种双功能蛋白，调节谷氨酸的表达。 转运蛋白可防止神经元中 NMDA 受体过度激活引起的神经毒性。 在戒除可卡因暴露期间，下调 GLT-1 和胱氨酸/谷氨酸交换剂。 伏隔核 (NAc) 中的 AMPA/NMDA 比率增加 NAc 是重要的大脑结构。 总体目标是研究 HIV-1 Nef 和可卡因成瘾之间的相互作用。 可卡因与谷氨酸稳态和药物寻求行为有关。 可卡因暴露和星形胶质细胞 Nef 表达会恶化谷氨酸兴奋诱导 神经生理学变化加强突触传递并强化寻求可卡因的行为。 为了解决这一假设，团队将制定以下两个具体目标 1：确定影响。 HIV-1 Nef 和可卡因对谷氨酸能神经传递的影响 目标 2：确定 HIV-1 Nef 对谷氨酸能神经传递的影响。 结合体内自我给药、电生理学和可卡因寻找行为。 通过使用脑组织进行分子研究，该团队将阐明 HIV-1 Nef 对可卡因寻求和依赖的作用 开发治疗艾滋病毒和 SUD 患者的新疗法至关重要。