Project 4

尽管很多研究都致力于甲基安非他明和HIV-1病毒诱导毒性的表征；关于急性和慢性冰毒对中枢神经系统功能完整性的神经生理影响以及HIV-1样感染与冰毒神经药理学的联合作用，我们知之甚少。阐明这些相互作用的细胞机制对于理解导致甲基苯丙胺和HIV-1诱导的神经毒性的神经生理事件序列至关重要，因此，以合理的方式确定甲基苯丙胺在HIV-1病毒感染中的潜在作用。本部分的目的是确定：(a)甲基苯丙胺对小鼠海马的影响是否与治疗计划和最后一次给药后的时间有关；(b)甲基苯丙胺是否会产生累加效应或协同效应，加速神经艾滋病患者功能缺陷的进展；(c)所选择的中枢神经系统促炎细胞因子（IL6, INFalpha）或HIV-1外壳蛋白gp120是否是甲基甲氧胺神经毒性和神经艾滋病发病机制之间协同作用的必要因素。我们将在体内和体外制备中使用细胞外和细胞内技术研究海马（CA1和齿状回）神经元。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制备。我们将确定它们的神经元兴奋性，膜和突触特性，局部电路相互作用和突触可塑性。此外，我们将描述海马突触可塑性和皮层下结构传入输入对海马齿状体功能的神经元调节作用。这些数据将有助于确定甲基苯丙胺治疗的基本特性，如甲基苯丙胺的剂量、甲基苯丙胺治疗的历史、癫痫发作活动的治疗阈值以及海马生理学。这些研究还将确定甲基苯丙胺与特定神经元群体和神经递质系统的特异性分离之间的相互作用，这些神经递质系统容易成为神经艾滋病和甲基苯丙胺神经药理学的目标。通过表征甲基安非他明治疗和HIV-1样感染对海马功能的影响，这些研究将为HIV-1样感染和甲基安非他明神经药理学的联合作用提供重要信息，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。

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.