Interactive effects of Meth, HIV and cART on astrocyte/neuron function

冰毒、HIV 和 cART 对星形胶质细胞/神经元功能的相互作用

• 批准号: 9750018
• 负责人: XIU-TI HU
• 金额: $ 49.59万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750018
• 关键词: AIDS/HIV problem; Acute; Address; Adult; Affect; Agonist; Amines; Anti-HIV Therapy; Astrocytes; Biological; Brain; Brain region; Cells; Chronic; Cognition; Combined Modality Therapy; Comorbidity; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Dopamine; Dose; Electrophysiology (science); Euphoria; Exposure to; Glutamates; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Human; Human Activities; Immunohistochemistry; In Vitro; Inflammation; Injections; Knowledge; Laboratory Animals; Lamivudine; Maintenance; Mathematics; Medial; Mediating; Medicine; Methamphetamine; Methamphetamine dependence; Modeling; Neuroglia; Neuronal Plasticity; Neurons; Outcome; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Pilot Projects; Play; Potassium Channel; Prefrontal Cortex; Proteins; Protocols documentation; Rattus; Relapse; Research; Resources; Self Administration; Signal Pathway; Testing; Training; Transgenic Organisms; Treatment Efficacy; Western Blotting; Withdrawal; abacavir; addiction; antiretroviral therapy; base; brain dysfunction; craving; dopaminergic neuron; drug abuser; drug of abuse; drug seeking behavior; drug testing; experience; extracellular; fetal; hippocampal pyramidal neuron; immune activation; improved; in vivo; methamphetamine abuse; methamphetamine effect; neurotoxicity; neurotransmission; novel; patch clamp; psychostimulant; receptor; reuptake; side effect

ABSTRACT Despite long-term combined antiretroviral therapy (cART), HIV+ drug abusers experience more severe and rapid progression of HIV-associated neurocognitive disorders (HAND). Methamphetamine (Meth) is a potent stimulant, which is highly abused in the USA, and associated with chronic systemic inflammation. Understanding the mechanism(s) by which Meth and HIV induce pathologies in the brain, whether and how chronic cART alters astrocyte/neuron function in the CNS, and whether Math (or other stimulants) affects cART, is critical for improving current, and developing new effective therapeutic strategies for treating Meth addiction and its comorbid conditions with HIV/AIDS. The medial prefrontal cortex (mPFC) is one of the key regulators of cognition and addiction; but it is profoundly altered following chronic Meth and HIV exposure in vivo with disrupted dopamine (DA) neurotransmission and immune activation of astrocytes. Both human and laboratory animal studies demonstrate that the mPFC dysregulation is significantly implicated in chronic Meth-induced brain dysfunction, associated with euphoria, craving, drug-taking and relapse. Cumulating evidence also indicates that both astrocytes and glutamatergic pyramidal neurons in the PFC are altered after chronic Meth or HIV exposure. Chronic Meth in vivo induces astrocytic and neuronal plasticity that differs from changes induced by acute Meth in vitro; but the underlying mechanism(s) of either one is not fully understood. In this proposed study, we will elucidate a novel, trace amine-associated receptor 1 (TAAR1)-mediated mechanism, by which acute Meth in vitro alters astrocyte activity; and determine alterations in this mechanism after Meth self-administration (Meth-SA) followed by a withdrawal (that elicits drug-seeking), in HIV-1 transgenic (Tg) or non-Tg rats. Moreover, we will also determine whether and how chronic cART in vivo affects functional activity of mPFC astrocytes and neurons; and whether such cART effects are altered by Meth-SA in the context of neuroHIV. Specifically, we will first define the mechanism by which chronic Meth in vivo alters astrocyte function (Aim1). We then will determine the mechanism by which Meth/HIV impacting on mPFC astrocytes/ neurons (Aim2). Finally, we will identify chronic effects of cART (using a fixed-dose combination of abacavir, dolutegravir and lamivudine) in vivo on mPFC astrocytes/neurons, and whether chronic Meth-SA alters them (Aim3). To prove the fundamental base of this proposed research, we provide justification, related citations, and preliminary data to support the Scientific Premise, Scientific Rigor, Relevant Biological Variables, and Resource Authentication for this proposal. Outcomes from the proposed research will reveal the novel, TAAR1- mediated mechanism that plays a key role in underlying the comorbid Meth/HIV impact, and chronic cART effects, on altering astrocytes and pyramidal neurons in the mPFC. This will advance our understanding for interactive effects of Meth, HIV and cART in the CNS, and therefore will induce a strong impact to the field.

抽象的 尽管长期联合抗逆转录病毒治疗 (cART)，HIV + 药物滥用者仍会经历更严重和更严重的症状。 HIV 相关神经认知障碍 (HAND) 的快速进展。甲基苯丙胺（Meth）是一种强效药物 兴奋剂，在美国被高度滥用，并与慢性全身炎症有关。 了解冰毒和艾滋病毒引起大脑病变的机制，是否以及如何引起的 慢性 cART 改变中枢神经系统中的星形胶质细胞/神经元功能，以及数学（或其他兴奋剂）是否影响 cART， 对于改善当前的情况并开发新的有效治疗策略来治疗冰毒成瘾至关重要 及其与艾滋病毒/艾滋病的合并症。内侧前额皮质 (mPFC) 是关键调节器之一 认知和成瘾；但在体内长期接触冰毒和艾滋病毒后，它会发生深刻的改变 破坏多巴胺（DA）神经传递和星形胶质细胞的免疫激活。人类和实验室 动物研究表明，mPFC 失调与甲基苯丙胺引起的慢性 大脑功能障碍，与欣快感、渴望、吸毒和复发有关。也不断积累证据 表明在长期使用冰毒后，前额皮质中的星形胶质细胞和谷氨酸能锥体神经元都发生了改变 或艾滋病毒暴露。体内慢性冰毒诱导星形胶质细胞和神经元可塑性不同于变化 体外急性甲基苯丙胺诱导；但其中任何一种的基本机制尚未完全了解。在这个 在拟议的研究中，我们将阐明一种新型的微量胺相关受体 1 (TAAR1) 介导的机制， 体外急性冰毒改变星形胶质细胞活性；并确定冰毒后该机制的改变 在 HIV-1 转基因 (Tg) 或 非Tg大鼠。此外，我们还将确定体内慢性 cART 是否以及如何影响功能活动 mPFC 星形胶质细胞和神经元；以及 Meth-SA 是否会改变这种 cART 效应 神经艾滋病毒。具体来说，我们将首先定义体内慢性冰毒改变星形胶质细胞的机制 功能（目标1）。然后我们将确定冰毒/HIV 影响 mPFC 星形胶质细胞/的机制 神经元（目标2）。最后，我们将确定 cART 的慢性影响（使用阿巴卡韦的固定剂量组合， 多替拉韦和拉米夫定）在体内对 mPFC 星形胶质细胞/神经元的影响，以及慢性 Meth-SA 是否会改变它们 （目标3）。为了证明这项拟议研究的基础，我们提供理由、相关引文、 以及支持科学前提、科学严谨性、相关生物变量的初步数据，以及 此提案的资源身份验证。拟议研究的结果将揭示新颖的 TAAR1- 介导机制在甲基苯丙胺/艾滋病毒共病影响和慢性 cART 中发挥关键作用 对改变 mPFC 中的星形胶质细胞和锥体神经元的影响。这将增进我们对 冰毒、艾滋病毒和 cART 在中枢神经系统中的相互作用，因此将对该领域产生强烈影响。