Methamphetamine Toxicity and Corticostriatal Glutamate

描述（由申请人提供）：甲基苯丙胺（冰毒）的不良影响是国际和国家关注的问题（SAMSHA, 2010；毒品和犯罪问题办公室，2010）。现在很清楚冰毒对人脑有毒性作用。动物研究已经为甲基安非他明的神经毒性机制和后果提供了有价值的信息，但甲基安非他明导致脑损伤的确切途径尚不清楚。人们普遍和合乎逻辑地认为，甲基安非他明的神经毒性作用源于其对大脑的直接作用。然而，在很大程度上被忽视的是可能导致甲基苯丙胺神经毒性的无数外周效应。这些影响的一个可能的外围来源是肝脏。众所周知，肝脏是甲基苯丙胺和其他滥用药物的直接目标，但没有考虑肝脏或其他周围器官损害是否与甲基苯丙胺神经毒性有关。然而，急性肝损伤的一个众所周知的后果是神经精神综合征，肝性脑病（HE）。HE的关键介质是高氨血症。氨（NH3）引起神经元损伤的机制与甲基安非他明诱导的神经毒性中涉及的兴奋性毒性和氧化应激非常相似。具体来说，NH3增加谷氨酸（GLU）的释放，激活NMDA受体，下调GLU转运蛋白，同时抑制谷氨酰胺合成酶（GLU的缩合），增加超氧自由基和一氧化氮的形成。基于令人兴奋的初步证据表明外周NH3与甲基苯丙胺的神经毒性作用有关，本提案将通过确定一种外周衍生的甲基苯丙胺诱导神经毒性的新介质来研究与甲基苯丙胺神经毒性相关的新概念。长期目标是确定冰毒神经毒性的决定因素，以评估反复接触冰毒对人类健康的风险。目的是阐明甲基安非他明引起多巴胺（DA）末端损伤的机制。核心假设是甲基苯丙胺引起高氨状态，引发GLU稳态、兴奋毒性和对GLU和DAergic调节蛋白的氧化应激的相互依赖和趋同改变。这些变化反过来促进了一个前馈过程，最终导致经典的冰毒神经毒性。特异性目的1将确定NH3是甲基甲醚诱导的DA末端损伤的介质，而特异性目的2将阐明NH3在甲基甲醚诱导的DA损伤中的兴奋毒性/谷氨酸能机制。具体目标3将建立在其他目标的基础上，并确定NH3是否通过GLU传输失调导致DA末端的氧化应激。总的来说，这些发现应该具有积极的影响，因为外周NH3作为甲基苯丙胺的小分子介质的鉴定可以为甲基苯丙胺过量和神经毒性的治疗提供可行的治疗策略，同时从根本上推进药物性脑损伤领域。该建议强调了外周器官毒性在介导神经系统后果中的广泛意义。

DESCRIPTION (provided by applicant): The adverse effects of methamphetamine (METH) are of international and national concern (SAMSHA, 2010; UNODC, 2010). It is now clear the METH has toxic effects on the human brain. Animal studies have provided valuable information on the neurotoxic mechanisms and consequences of METH but the precise means by which METH causes brain damage remain unclear It is commonly and logically assumed that its neurotoxic effects are derived from its direct action on the brain. However, largely ignored are the myriad peripheral effects that might contribute to METH neurotoxicity. A likely peripheral source of these effects is the liver. It is known that the liver is a direct target of METH and man other drugs of abuse but no consideration has been given to whether liver or other peripheral organ damage is related to METH neurotoxicity. However, a well known consequence of acute liver damage is the neuropsychiatric syndrome, hepatic encephalopathy (HE). The key mediator of HE is hyperammonemia. Ammonia (NH3) causes neuronal damage through mechanisms strikingly similar to excitotoxicity and oxidative stress that have been implicated in METH-induced neurotoxicity. Specifically, NH3 increases glutamate (GLU) release, activates NMDA receptors, and down- regulates the GLU transporter, while inhibiting glutamine synthetase (condensation of GLU) and increasing superoxide radical and nitric oxide formation. This proposal will examine a new concept related to the neurotoxicity of METH by identifying a peripherally derived, novel mediator of METH-induced neurotoxicity based on exciting preliminary evidence implicating peripheral NH3 in the neurotoxic effects of METH. The long term goal is to identify the determinants of METH neurotoxicity to assess the risk to human health of repeated METH exposures. The objective is to elucidate the mechanisms by which METH causes damage to dopamine (DA) terminals. The central hypothesis is that METH causes a hyperammonemic state that triggers interdependent and convergent alterations in GLU homeostasis, excitotoxicity, and oxidative stress to GLUergic and DAergic regulatory proteins. These changes in turn, promote a feed-forward process that culminates in the classical METH neurotoxicity. Specific Aim 1 will identify NH3 as a mediator of METH-induced damage to DA terminals while Specific Aim 2 will elucidate the excitotoxic/glutamatergic mechanisms underlying the effects of NH3 in METH- induced damage to DA. Specific Aim 3 will build upon the other aims and determine if NH3 contributes to oxidative stress to DA terminals through a dysregulation of GLU transmission. Overall, the findings should have a positive impact because the identification of peripheral NH3 as a small molecule mediator of METH can lead to feasible therapeutic strategies for the treatment of METH overdose and neurotoxicity while fundamentally advancing the field of drug-induced brain damage in general. The proposal highlights the broader significance of peripheral organ toxicity in mediating neurological consequences.