Chronic Cocaine Exposure & HIV-1 Tat: Dysregulation of the Medical Prefrontal Cor

长期接触可卡因

• 批准号: 7686005
• 负责人: XIU-TI HU
• 金额: $ 15万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686005
• 关键词: AIDS Dementia Complex; AIDS/HIV problem; AMPA Receptors; Acquired Immunodeficiency Syndrome; Action Potentials; Affect; Applications Grants; Astrocytes; Behavior Control; Behavioral; Behavioral Model; Biological; Brain; Brain region; Cell Culture Techniques; Cell Death; Cells; Cessation of life; Chronic; Clinical Trials; Cocaine; Cocaine Abuse; Cocaine Dependence; Cognitive; Comorbidity; Corpus striatum structure; Data; Disease; Dose; Evaluation; Exposure to; Functional disorder; Future; Generations; Glutamate Receptor; Goals; HIV; HIV Infections; HIV tat Protein; HIV-1; Impaired cognition; In Vitro; Individual; Judgment; Lead; Medial; Mediating; Medical; Membrane; Membrane Potentials; Microglia; Morbidity - disease rate; N-Methylaspartate; Nerve Degeneration; Neurocognitive; Neurons; Neuropathogenesis; Nifedipine; Pathogenesis; Pathology; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Pilot Projects; Predisposition; Prefrontal Cortex; Process; Proteins; Protocols documentation; Pyramidal Cells; Rattus; Records; Relative (related person); Research Design; Rest; Rewards; Risk; Role; Saline; Slice; Societies; System; Testing; Time; Translating; Up-Regulation; Viral Proteins; Work; addiction; base; channel blockers; cocaine exposure; cognitive function; design; dopamine system; effective therapy; excitotoxicity; hippocampal pyramidal neuron; in vivo; innovation; macrophage; monocyte; mortality; motor deficit; neuroadaptation; neurotoxic; novel; pre-clinical research; progressive neurodegeneration; psychosocial; public health relevance; research study; response; tat Protein; therapeutic target; virotoxins

DESCRIPTION (provided by applicant): Dysregulation and progressive neurodegeneration in the prefrontal cortex of HIV/AIDS patients affect cognitive function and are implicated in HIV-associated neurocognitive disorders (HAND), including HIV- associated dementia (HAD). Although the precise mechanisms that underlie HAD/HAND remain unknown, HIV-1 viral proteins are most likely involved. A prominent example is HIV-1 Tat (Tat), a HIV-1 transactivating protein, causes dysregulation and ultimately death of cortical/striatal neurons and astrocytes in vitro. In the brain, Tat is released by HIV-infected microglia, macrophages and monocytes. The neurotoxic effects of Tat in vitro result from an excessive increase of cytosolic free Ca2+ levels caused by abnormally enhanced Ca2+ influx via L-type Ca2+ channels, activation of ionotropic glutamate receptors and intracellular Ca2+ release. Cocaine abuse increases the morbidity and mortality of HIV/AIDS-associated pathology with exacerbation of cognitive, psychosocial and motor deficits. Even though the medial prefrontal cortex (mPFC) is well- recognized as a critical brain region in the control of these behaviors, as well as of addiction, the mechanisms underlying its dysregulation in the cocaine abuse-HIV/AIDS comorbidity have not been examined. Also, current HIV/AIDS studies predominantly focus on cell cultures, thus, the circuit-related processes are unknown. These two situations have delayed our understanding of the neuropathogenesis of this comorbidity. Our recent work with rats demonstrate that chronic cocaine exposure significantly increases Ca2+ influx by selectively upregulating L-type Ca2+ channel function in pyramidal neurons localized in the mPFC. These novel findings strongly suggest that chronic exposure to cocaine in vivo may potentiate the dysregulation and consequent neurodegeneration of the mPFC induced by Tat. Based on these evidences, the objective of the current project is to ascertain a common biological substrate in the mPFC for cocaine abuse on HIV/AIDS. The designed experiments will test the hypothesis that chronic cocaine exposure in vivo increases susceptibility and vulnerability of the mPFC to HIV-1 Tat by increasing Ca2+ influx via L-type Ca2+ channels in pyramidal cells, and these changes contribute to the pathogenesis of cocaine abuse and HAD. This pilot study is innovative and significant because it will provide informative preliminary data pointing to the mechanisms underlying the cocaine abuse-HAD comorbidity. Results from these studies will used to develop a R01 application focusing on this comorbidity and putative therapeutic targets to help treat dually afflicted individuals. PUBLIC HEALTH RELEVANCE: This grant application is titled: "Chronic cocaine exposure & HIV-1 Tat: Dysregulation of the medial prefrontal cortex." Our goal is to explore the mechanisms of the brain and behavioral deficits induced by cocaine abuse and HIV infection. The combination of these two problems results in a much more severe condition, and unfortunately the combination is spreading in our society. This project will determine how a protein (Tat) produced by HIV-infected cells alters activity of neurons in the medial prefrontal cortex. This brain region is involved both in reward and in judgment, and it is compromised in both cocaine addiction and AIDS. We propose that changes in neuronal activity in the medial prefrontal cortex induced by the HIV protein Tat will be potentiated by repeated cocaine exposure. Findings from this study will help us to verify the common target of cocaine abuse and HIV infection, which will be very important for developing more effective treatments for cocaine abuse and HIV-related brain/behavioral deficits.

描述（由申请人提供）：HIV/AIDS患者前额叶皮层的失调和进行性神经退行性变影响认知功能，并与HIV相关的神经认知障碍（HAND）有关，包括HIV相关痴呆（HAD）。虽然HAD/HAND的确切机制尚不清楚，但HIV-1病毒蛋白很可能参与其中。一个突出的例子是HIV-1 Tat (Tat)，一种HIV-1反激活蛋白，在体外导致皮质/纹状体神经元和星形胶质细胞失调并最终死亡。在大脑中，Tat由感染hiv的小胶质细胞、巨噬细胞和单核细胞释放。Tat在体外的神经毒性作用是由于通过l型Ca2+通道异常增强的Ca2+内流引起的胞质游离Ca2+水平过度增加，激活嗜离子性谷氨酸受体和细胞内Ca2+释放。可卡因滥用增加了艾滋病毒/艾滋病相关病理的发病率和死亡率，并加剧了认知、社会心理和运动缺陷。尽管内侧前额叶皮层（mPFC）被公认为是控制这些行为和成瘾的关键大脑区域，但其在可卡因滥用-艾滋病毒/艾滋病共病中的失调机制尚未得到研究。此外，目前的艾滋病毒/艾滋病研究主要集中在细胞培养上，因此，电路相关的过程是未知的。这两种情况延迟了我们对这种合并症的神经发病机制的理解。我们最近对大鼠的研究表明，慢性可卡因暴露通过选择性上调位于mPFC的锥体神经元中的l型Ca2+通道功能，显著增加Ca2+内流。这些新发现强烈表明，体内长期暴露于可卡因可能会加剧由Tat引起的mPFC失调和随之而来的神经退行性变。根据这些证据，目前项目的目标是确定mPFC中可卡因滥用对艾滋病毒/艾滋病的共同生物学基础。设计的实验将验证体内慢性可卡因暴露通过增加锥体细胞中l型Ca2+通道的Ca2+内流增加mPFC对HIV-1 Tat的易感性和脆弱性的假设，这些变化有助于可卡因滥用和HAD的发病机制。这项初步研究具有创新性和重要意义，因为它将提供信息丰富的初步数据，指出可卡因滥用- had合并症的潜在机制。这些研究的结果将用于开发R01应用程序，重点关注这种合并症和假定的治疗靶点，以帮助治疗双重患者。公共卫生相关性：这项拨款申请的标题是：“慢性可卡因暴露与HIV-1 Tat：内侧前额皮质失调”。我们的目标是探索可卡因滥用和艾滋病毒感染引起的大脑和行为缺陷的机制。这两个问题的结合导致了更严重的情况，不幸的是，这种结合正在我们的社会中蔓延。该项目将确定hiv感染细胞产生的蛋白质（Tat）如何改变内侧前额皮质神经元的活动。这个大脑区域与奖励和判断有关，在可卡因成瘾和艾滋病中都受到损害。我们提出，由HIV蛋白Tat引起的内侧前额叶皮层神经元活动的变化将因反复暴露于可卡因而增强。这项研究的发现将有助于我们验证可卡因滥用和艾滋病毒感染的共同目标，这将对开发更有效的治疗可卡因滥用和艾滋病毒相关的大脑/行为缺陷非常重要。