Methamphetamine Neurotoxity and Microglial Activation

描述（由申请人提供）：甲基苯丙胺（冰毒）滥用已达到惊人的程度，导致包括NIDA， ONDCP和DEA在内的许多联邦机构将其比作流行病。与任何药物滥用相关的医疗、法律和社会问题在冰毒的情况下都是复杂的，因为它会对多巴胺（DA）神经系统造成持续的损害。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，神经毒性会增强。大脑中唯一能有效感染艾滋病毒的细胞是小胶质细胞。这项提议的长期目标是更好地理解甲基安非他明施加神经毒性的机制。我们假设甲基苯丙胺中毒导致小胶质细胞激活。受损的DA神经末梢和激活的小胶质细胞之间的串扰产生并延续了一个恶性循环，最终导致DA神经毒性。我们提出了5个具体目标来验证我们的假设：1)确定甲基苯丙胺诱导的小胶质细胞活化的药理学特征；2)确定COX-2、PGE2和DA醌在甲基苯丙胺毒性中的作用；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）对甲基安非他明毒性的影响；4)确定尼古丁和？9 -四氢大麻酚（THC）通过与小胶质细胞上的同源受体相互作用来保护甲基苯丙胺的毒性；5)用活化的小胶质细胞培养基培养稳定表达DA转运体的哺乳动物细胞，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，以及用培养的小鼠小胶质细胞进行平行研究，以评估小胶质细胞与冰毒毒性的关系。更好地了解甲基苯丙胺对DA神经元系统造成持续损害的机制，可能会导致更有针对性的治疗方法，并将为甲基苯丙胺和其他滥用神经毒性药物的研究开辟新的途径。

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.