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

摘要 尽管长期联合抗逆转录病毒治疗（cART），艾滋病毒+药物滥用者经历更严重， HIV相关的神经认知障碍（HAND）的快速进展。甲基苯丙胺（Methamphetamine）是一种强效的 兴奋剂，这是高度滥用在美国，并与慢性全身炎症。 了解冰毒和艾滋病毒在大脑中诱导病理的机制，是否以及如何 慢性cART改变CNS中的星形胶质细胞/神经元功能，以及Math（或其他兴奋剂）是否影响cART， 对于改善目前的治疗方法和开发新的有效的治疗策略来治疗冰毒成瘾至关重要 及其与艾滋病毒/艾滋病的共病情况。内侧前额叶皮层（mPFC）是一个关键的调节器 认知和成瘾;但在体内长期接触冰毒和艾滋病毒后，这种情况发生了深刻的改变， 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失调与慢性Meth-induced 大脑功能障碍，与欣快、渴望、吸毒和复发有关。累积的证据也 表明在慢性甲基苯丙胺中毒后，PFC中的星形胶质细胞和多巴胺能锥体神经元都发生了改变。 或者艾滋病病毒感染体内慢性甲基苯丙胺诱导星形胶质细胞和神经元可塑性， 在体外由急性甲基诱导;但任何一种的潜在机制都不完全清楚。在这 提出的研究，我们将阐明一种新的，痕量胺相关受体1（TAAR 1）介导的机制， 急性甲基在体外改变星形胶质细胞的活性;并确定甲基后这种机制的改变 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性， 的mPFC星形胶质细胞和神经元;以及在mPFC星形胶质细胞和神经元的背景下，Meth-SA是否改变了这种cART效应。 神经HIV。具体来说，我们将首先确定慢性甲基苯丙胺在体内改变星形胶质细胞的机制， 函数（Aim 1）。然后，我们将确定甲基/艾滋病病毒影响mPFC星形胶质细胞的机制。 神经元（Aim 2）。最后，我们将确定cART的慢性效应（使用阿巴卡韦的固定剂量组合， dolutegravir和lamivudine）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）。为了证明这项研究的基本基础，我们提供了理由，相关引文， 以及支持科学假设、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的TAAR 1- 介导的机制，在Meth/HIV共病影响和慢性cART的基础上发挥关键作用 影响，改变mPFC中的星形胶质细胞和锥体神经元。这将促进我们对 因此，本研究将对该领域产生强烈的影响。

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.