Project 4

项目4

• 批准号: 6594214
• 负责人: GEORGE Robert SIGGINS
• 金额: $ 35.07万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6594214
• 关键词: AIDS /HIV neuropathy; HIV envelope protein gp120; cell population study; cytokine; drug administration rate /duration; drug interactions; hippocampus; human immunodeficiency virus 1; inflammation; interferon alpha; interleukin 6; laboratory mouse; methamphetamine; neural plasticity; neuropharmacology; tumor necrosis factor alpha; virus infection mechanism

Though much research has been devoted to the characterization of METH- and HIV-1 viral-induced toxicity; very little is known about the neurophysiological effects of acute and chronic METH on the functional integrity of the CNS and the combined effects of HIV-1 like infection with METH neuropharmacology. Elucidating the cellular mechanisms responsible for these interactions is essential for understanding the sequence of neurophysiological events leading to METH and HIV-1- induced neurotoxicity and thus,, determining in a rational manner, the potential role of METH in HIV-1 viral infection. The objectives of our component are to determine: (a) whether the effects of METH on the murine hippocampus are a function of the treatment schedule and the time following the last drug administration; (b) whether METH produces additive or synergistic effects accelerating the progression of the functional deficits of NeuroAIDS; and (c) whether selected CNS pro- inflammatory cytokines (IL6, INFalpha) or the HIV-1 coat protein gp120 are essential elements in the synergy between METH neurotoxicity and NeuroAIDS pathogenesis. We will study hippocampal (CA1 and dentate gyrus) neurons using extracellular and intracellular techniques in both in vivo and in vitro preparations. We will determine their neuronal excitability, membrane, membrane and synaptic properties and in vitro preparations. We will determine their neuronal excitability, membrane and synaptic properties, local circuit interactions and synaptic plasticity. In addition, we will characterize hippocampal synaptic plasticity and the neuronal modulatory effects of afferent inputs from subcortical structures on hippocampal dentate function in vivo. These data will help determine whether basic properties of the METH treatment such as the dose of METH, the history of METH treatment, the treatment threshold for seizure activity, and on hippocampal physiology. The studies will also identify the interactions between METH and of specific isolation of specific neuronal populations and neurotransmitter systems prone to be targets of NeuroAIDS and METH neuropharmacology. By characterizing the effects of METH treatment and HIV-1-like infection on hippocampal function, these studies will contribute important information about the combined effects of HIV-1 like infection and METH neuropharmacology and will provide critical data for the future identification of beneficial approaches for the treatment and prevention of these conditions.

虽然对冰毒和HIV-1病毒诱导的毒性进行了大量研究，但对急性和慢性冰毒对中枢神经系统功能完整性的神经生理学影响以及类似HIV-1感染与冰毒神经药理学的联合影响知之甚少。阐明这些相互作用的细胞机制对于了解导致冰毒和HIV-1诱导的神经毒性的神经生理事件的顺序，从而合理地确定冰毒在HIV-1病毒感染中的潜在作用是至关重要的。我们这个组成部分的目标是确定：(A)冰毒对小鼠海马区的影响是否是最后一次给药后治疗时间表和时间的函数；(B)冰毒是否能产生相加或协同作用，加速神经艾滋病功能缺陷的进展；以及(C)选定的中枢神经系统促炎细胞因子(IL6，INFpha)或HIV-1外壳蛋白gp120是否是冰毒神经毒性和神经艾滋病发病机制之间协同作用的基本元素。我们将在体内和体外准备中使用细胞外和细胞内技术研究海马神经元(CA1和齿状回)。我们将测定它们的神经元兴奋性、膜、膜和突触特性以及体外准备。我们将测定它们的神经元兴奋性、膜和突触特性、局部回路相互作用和突触可塑性。此外，我们还将在体内研究海马区突触的可塑性以及皮质下结构传入信息对海马齿状回功能的神经调节作用。这些数据将有助于确定冰毒治疗的基本性质，如冰毒剂量、冰毒治疗史、癫痫发作的治疗阈值以及对海马区生理的影响。这些研究还将确定冰毒与特定神经元群体和神经递质系统的特定隔离之间的相互作用，这些神经群体和神经递质系统容易成为神经艾滋病和冰毒神经药理学的靶标。通过表征冰毒治疗和类HIV-1感染对海马区功能的影响，这些研究将有助于了解HIV-1类感染和冰毒神经药理学的联合影响，并将为未来确定治疗和预防这些疾病的有益方法提供关键数据。