Methamphetamine Toxicity and Corticostriatal Glutamate

说明(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年；禁毒办，2010年)。现在很明显，冰毒对人类的大脑有毒性影响。动物研究已经为冰毒的神经毒性机制和后果提供了有价值的信息，但冰毒导致脑损伤的确切方式仍不清楚，通常从逻辑上认为，其神经毒性效应来自于它对大脑的直接作用。然而，很大程度上被忽视的是可能导致冰毒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，肝脏是冰毒和人类滥用其他药物的直接目标，但尚未考虑肝脏或其他外周器官损伤是否与冰毒神经毒性有关。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)。高氨血症是肝性脑病的关键介质。氨(NH3)通过与兴奋性毒性和氧化应激极其相似的机制导致神经元损伤，而兴奋性毒性和氧化应激与冰毒诱导的神经毒性有关。具体地说，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)，增加超氧阴离子自由基和一氧化氮的形成。这项提案将基于令人兴奋的初步证据表明外周NH3与冰毒的神经毒性作用有关，通过确定一种外周派生的新的冰毒诱导的神经毒性介质来检验与冰毒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。目的是阐明冰毒对多巴胺(DA)终末的损害机制。中心假设是，冰毒引起高氨化状态，触发GLU稳态、兴奋性毒性和氧化应激对GLU和DAR能调节蛋白的相互依赖和趋同的改变。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。特异性目标1将确定NH3是冰毒诱导的DA终末损伤的媒介，而特异性目标2将阐明NH3在冰毒诱导的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传递的失调而导致DA终末的氧化应激。总体而言，这些发现应该会产生积极的影响，因为将外周NH3确定为冰毒的小分子媒介可以为冰毒过量和神经毒性的治疗提供可行的治疗策略，同时从根本上促进药物诱导的脑损伤领域的整体发展。该提案强调了外周器官毒性在调节神经后果方面的更广泛意义。

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.