Methamphetamine Neurotoxity and Microglial Activation

甲基苯丙胺神经毒性和小胶质细胞激活

• 批准号: 7022957
• 负责人: Donald M Kuhn
• 金额: $ 22.12万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7022957
• 关键词: body temperature; cannabinoids; confocal scanning microscopy; dextromethorphan; dopamine; dopamine transporter; drug abuse; gene expression; genetically modified animals; laboratory mouse; methamphetamine; microglia; neurons; neurophysiology; neurotoxicology; nicotine; prostaglandin E; prostaglandin endoperoxide synthase; protein structure function; quinones; tissue /cell culture; transcription factor; virus protein

DESCRIPTION (provided by applicant): Methamphetamine (METH) abuse has reached alarming proportions, leading numerous federal agencies including NIDA, ONDCP, and the DEA to liken it to an epidemic. The medical, legal, and societal problems associated with any drug of abuse are compounded in the case of METH because it causes persistent damage to the dopamine (DA) neuronal system. Nowhere is this more evident than in individuals with AIDS, who show heightened neurotoxicity when they also abuse METH. The only cells in brain that are productively infected with HIV are microglia. The long-term objective of this proposal is to achieve a better understanding of the mechanisms by which METH exerts neurotoxicity. We hypothesize that METH intoxication leads to microglial activation. The ensuing cross-talk between distressed DA nerve endings and activated microglia, which secrete numerous species capable of damaging neurons, creates and perpetuates a vicious cycle that culminates in DA neurotoxicity. We propose 5 specific aims to test our hypotheses: 1) determine the pharmacological characteristics of methamphetamine-induced activation of microglia; 2) determine the role of COX-2, PGE2, and DA quinones in METH toxicity; 3) determine the influence of microglial status (activated by the neurotoxic HIV TAT protein or inhibited by non-competitive NMDA antagonists) on METH toxicity; 4) determine if nicotine and ?9 -tetrahydrocannabinol (THC) protect against METH toxicity through interaction with their cognate receptors on microglia; and 5) determine how microglial activation influences DAT function by culturing mammalian cells stably expressing the DA transporter with media from activated microglia. The experimental approach to these studies will combine neurochemistry, neuropharmacology, laser scanning microscopy, use of knock-out mice, and parallel studies with cultured mouse microglia cells to evaluate microglial involvement in METH toxicity. A better understanding of the mechanisms by which METH causes persistent damage to the DA neuronal system could lead to more targeted therapies and would open newer lines of investigation into this and other neurotoxic drugs of abuse.

描述（由申请人提供）：甲基苯丙胺 (METH) 滥用已达到惊人的程度，导致包括 NIDA、ONDCP 和 DEA 在内的众多联邦机构将其比作流行病。与滥用药物相关的医疗、法律和社会问题在冰毒的情况下更加复杂，因为它会对多巴胺 (DA) 神经元系统造成持续损害。这一点在艾滋病患者身上表现得最为明显，当他们同时滥用冰毒时，就会表现出更高的神经毒性。大脑中唯一有效感染艾滋病毒的细胞是小胶质细胞。该提案的长期目标是更好地了解冰毒发挥神经毒性的机制。我们假设冰毒中毒会导致小胶质细胞激活。随后，受损的 DA 神经末梢和激活的小胶质细胞之间会发生相互作用，小胶质细胞会分泌大量能够损害神经元的物质，从​​而形成并维持恶性循环，最终导致 DA 神经毒性。我们提出了 5 个具体目标来检验我们的假设：1）确定甲基苯丙胺诱导的小胶质细胞激活的药理学特征； 2)确定COX-2、PGE2和DA醌在METH毒性中的作用； 3) 确定小胶质细胞状态（由神经毒性 HIV TAT 蛋白激活或由非竞争性 NMDA 拮抗剂抑制）对 METH 毒性的影响； 4) 确定尼古丁和 9-四氢大麻酚 (THC) 是否通过与其小胶质细胞上的同源受体相互作用来防止冰毒毒性； 5) 通过使用来自活化小胶质细胞的培养基培养稳定表达 DA 转运蛋白的哺乳动物细胞，确定小胶质细胞活化如何影响 DAT 功能。这些研究的实验方法将结合神经化学、神经药理学、激光扫描显微镜、基因敲除小鼠的使用以及培养小鼠小胶质细胞的平行研究，以评估小胶质细胞参与冰毒毒性。更好地了解冰毒对 DA 神经元系统造成持续损伤的机制可能会导致更有针对性的治疗，并将为这种药物和其他神经毒性药物滥用开辟新的研究方向。