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: 10199988
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199988
• 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; 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; Western Blotting; Withdrawal; abacavir; addiction; antiretroviral therapy; base; brain dysfunction; comorbidity; 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; neuroAIDS; neurotoxicity; neurotransmission; novel; patch clamp; psychostimulant; receptor; reuptake; side effect; systemic inflammatory response; therapeutically effective

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.

摘要 尽管长期联合抗逆转录病毒疗法(CART)，艾滋病毒+吸毒者经历了更严重和 艾滋病毒相关神经认知障碍的快速进展(手)。甲基苯丙胺(Meth)是一种有效的 兴奋剂，在美国被高度滥用，与慢性全身炎症有关。 了解甲基苯丙胺和艾滋病毒在大脑中引起病理的机制(S)，是否以及如何 慢性CART改变了中枢神经系统中星形胶质细胞/神经元的功能，以及Math(或其他兴奋剂)是否影响CART， 对于改善目前的情况，并开发新的有效的治疗策略来治疗冰毒成瘾至关重要 以及它与艾滋病毒/艾滋病的共生条件。内侧前额叶皮质(MPFC)是中枢神经系统的重要调节器之一 认知和成瘾；但在体内长期接触Meth和HIV后，它发生了深刻的变化 破坏了多巴胺(DA)的神经传递和星形胶质细胞的免疫激活。无论是人类还是实验室 动物研究表明，mPFC的失调与慢性Meth诱导的 大脑功能障碍，与欣快感、渴求、吸毒和复发有关。累积的证据也 提示慢性甲基化后前额叶星形胶质细胞和谷氨酸能锥体神经元均发生改变。 或者是艾滋病病毒暴露。体内慢性蛋氨酸诱导的星形胶质细胞和神经元可塑性不同于改变 在体外由急性蛋氨酸诱导，但两者的潜在机制(S)尚未完全了解。在这 在拟议的研究中，我们将阐明一种新的、示踪胺相关受体1(TAAR1)介导的机制， 体外急性Meth改变星形胶质细胞活性的机制；并确定Meth后这一机制的改变 自我给药(Meth-SA)后停药(这会导致药物寻求)，在HIV-1转基因(TG)或 非甘油三酯大鼠。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的表达；以及这种CART效应是否被Meth-SA在 神经艾滋病毒。具体地说，我们将首先定义体内慢性蛋氨酸改变星形胶质细胞的机制 函数(Aim1)。然后我们将确定Meth/HIV影响mPFC星形胶质细胞的机制。 神经元(AIM2)。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， 多洛替格韦和拉米夫定)在体内对mPFC星形胶质细胞/神经元的影响以及慢性Meth-SA是否改变它们 (目标3)。为了证明这项拟议研究的基本基础，我们提供了理由、相关引用、 和初步数据，以支持科学前提、科学严谨性、相关生物变量，以及 此建议的资源身份验证。这项拟议研究的结果将揭示这部小说，TAAR1- 在共同感染Meth/HIV的影响下发挥关键作用的中介机制，以及慢性CART 对mPFC内星形胶质细胞和锥体神经元的影响。这将增进我们对 Meth、HIV和CART在中枢神经系统的相互作用，因此将对该领域产生强烈影响。

项目成果

Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons.

• DOI: 10.1016/j.nbd.2016.06.008
• 发表时间: 2016-10
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Khodr CE;Chen L;Dave S;Al-Harthi L;Hu XT
• 通讯作者: Hu XT

Enhanced neuronal and blunted hemodynamic reactivity to cocaine in the prefrontal cortex following extended cocaine access: optical imaging study in anesthetized rats.

• DOI: 10.1111/adb.12615
• 发表时间: 2019-05
• 期刊: Addiction biology
• 影响因子: 3.4
• 作者: Allen CP;Park K;Li A;Volkow ND;Koob GF;Pan Y;Hu XT;Du C
• 通讯作者: Du C

Cortical consequences of HIV-1 Tat exposure in rats are enhanced by chronic cocaine.

• DOI: 10.2174/0929867322666150311164504
• 发表时间: 2015
• 期刊: Current HIV research
• 影响因子: 1
• 作者: Wayman WN;Chen L;Persons AL;Napier TC
• 通讯作者: Napier TC

Cocaine self-administration enhances excitatory responses of pyramidal neurons in the rat medial prefrontal cortex to human immunodeficiency virus-1 Tat.

• DOI: 10.1111/ejn.12853
• 发表时间: 2015-05
• 期刊: The European journal of neuroscience
• 作者: Wayman WN;Chen L;Napier TC;Hu XT
• 通讯作者: Hu XT

HIV-1 Transgenic Rat Prefrontal Cortex Hyper-Excitability is Enhanced by Cocaine Self-Administration.

HIV-1 转基因大鼠前额叶皮层的过度兴奋性通过可卡因自我给药而增强。

• DOI: 10.1038/npp.2015.366
• 发表时间: 2016
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Wayman,WesleyN;Chen,Lihua;Hu,Xiu-Ti;Napier,TCeleste
• 通讯作者: Napier,TCeleste