Impacts of morphine and HIV-Tat exposures and dimethylfumarate treatment on brain BDNF and mitochondrial and behavioral dysfunction.

摘要/摘要 去年有75,000多例药物过量死亡与阿片类药物有关。为了应对这种流行病， NIH已优先开发更有效的阿片使用障碍(OUD)治疗方法，如目前 干预措施是有帮助的，但还不够。OUD在人类免疫缺陷患者中很常见 病毒(HIV)和共病/HIV增加了心理和身体健康损害的风险 严肃性。因此，共病的艾滋病患者构成了一个弱势群体，必须进行基础研究。 与这一群体相关的因素。我们和其他人的数据表明，当阿片类药物和艾滋病毒结合在一起时 蛋白质诱导趋同的有害效应，可能导致有问题的阿片类药物使用行为和 损害一般人的健康。这项基础科学R01计划旨在填补个人和 典型阿片类药物、吗啡和HIV转录反式激活因子(TAT)蛋白的联合作用 线粒体功能、脑源性神经营养因子(BDNF)表达以及对动物行为的影响，包括 这些类似于人类行为的研究缓解了OUD和伴发疾病患者的健康结局 奥德/艾滋病毒。提高我们对Tat蛋白作用的理解对于更好地理解HIV的作用是至关重要的 因为尽管在艾滋病抗逆转录病毒治疗(ART)期间几乎完全抑制了病毒，但TAT是可以检测到的 40%的接受抗逆转录病毒治疗的患者在一年的过程中至少进行一次重复检测。这事很重要 由于TAT在动物体内的表达诱导出与艾滋病毒携带者身上观察到的表型相似的表型， 包括焦虑、抑制控制以及大脑结构和功能缺陷。TAT的相关性 在我们的飞行员行为数据中说明了OUD/HIV并存，表明TAT放大了吗啡的摄入， 寻求和灭绝后的复活。我们还测试了富马酸二甲酯(DMF)的效果，我们有 缓解吗啡戒断症状。对感染SIV的猕猴的研究报告DMF保护 线粒体和其他研究表明，DMF刺激BDNF信号转导。我们关注线粒体是因为 它们提供了神经元和高级大脑功能所需的大部分能量，它们受到 OUD或HIV感染者体内的吗啡、TAT和人脑。我们的假设是吗啡， Tat，以及它们的结合将增加吗啡的自我管理，损害学习、记忆和认知 用磷(31P)磁共振评估体内脑线粒体功能的灵活性 光谱，并将降低包括核呼吸因子1在内的线粒体生物发生因子的水平 和2的表达，如死后确定。DMF，通过保护线粒体和增加BDNF 水平，将限制吗啡和纹身的有害影响。这项基础科学计划旨在填补重要的 关于阿片类药物、TAT和DMF的个体和联合影响的知识差距，并可能产生以下数据 支持我们和包括DMF在内的其他人研究的治疗艾滋病和艾滋病的新方法的应用研究。

Summary/Abstract More than 75,000 drug overdose deaths this past year were associated with opioids. To address this epidemic, NIH has prioritized the development of more effective opioid use disorder (OUD) treatments, as current interventions are helpful but inadequate. OUD is common among people living with Human Immunodeficiency Virus (HIV) and comorbid OUD/HIV increases risk for mental and physical health impairments of greater severities. Thus, comorbid OUD/HIV patients constitute a vulnerable group and basic research must study factors relevant to this group. We and others have data indicating that when combined, opioids and HIV proteins induce convergent deleterious effects that likely engender problematic opioid use behaviors and impair general health. This basic science R01 program aims to fill knowledge gaps in the individual and combined effects of the prototypical opioid, morphine, and HIV transactivator of transcription (Tat) protein, on mitochondrial function, brain derived neurotrophic factor (BDNF) expression, and on animal behavior, including those analogous to human behaviors that moderate health outcomes in patients with OUD and comorbid OUD/HIV. Improving our understanding of Tat protein’s effects is critical to better understanding effects of HIV because despite nearly complete viral suppression during antiretroviral therapy for HIV (ART), Tat is detectible with repeat testing in 40% of ART-treated patients at least once over the course of a year. This is important because Tat expression in animals induces phenotypes analogous to those observed in people living with HIV, including impairments in anxiety, inhibitory control, and brain structural and functional deficits. Tat’s relevance to comorbid OUD/HIV is illustrated in our pilot behavioral data indicating that Tat amplifies morphine taking, seeking, and post-extinction reinstatement. We also test effects of dimethylfumarate (DMF), which we have shown moderates morphine withdrawal symptoms. Studies in SIV-infected macaques report that DMF protects mitochondria and other studies show that DMF stimulates BDNF signaling. We focus on mitochondria because they supply most of the energy needed for neuronal and higher order brain function and they are impaired by morphine, Tat, and in human brain in vivo in people with OUD or HIV. Our working hypothesis is that morphine, Tat, and their combination will increase morphine self-administration, impair learning, memory, and cognitive flexibility, impair in vivo brain mitochondrial function assessed with phosphorus (31P) magnetic resonance spectroscopy, and will lower levels of mitochondrial biogenesis factors including Nuclear Respiratory Factor 1 and 2 expression, as determined postmortem. DMF, by protecting mitochondria and by increasing BDNF levels, will limit morphine’s and Tat’s deleterious effects. This basic science program aims to fill important knowledge gaps on the individual and combined effects of opioids, Tat, and DMF, and could yield data that support applied studies of novel treatments for OUD and HIV studied by us and by others, including DMF.