METHAMPHETAMINE TOXICITY AND CORTICOSTRIATAL GLUTAMATE

甲基苯丙胺(冰毒)是一种滥用药物，对 中枢神经系统包括精神运动激活和情绪提升。这些影响 都导致了其高度的滥用责任。此外，长时间使用 产生了一种类似偏执型精神分裂症的行为模式。这些 行为副作用和滥用可能性表明，冰毒会产生 中枢神经系统的长期神经毒性效应。然而，确切的机制是 冰毒对多巴胺神经元的损伤机制尚不清楚。兴奋性氨基酸 如谷氨酸等与冰毒引起的脑血管紧张素转换酶的耗竭有关 多巴胺。 这项建议的主要目的是阐明 潜在的冰毒毒性，并关注谷氨酸依赖的机制 以及介导冰毒对纹状体多巴胺的毒性效应的反应 神经元。谷氨酸传递和内毒素的药理作用 细胞外多巴胺和谷氨酸浓度的活体测量 将采用微渗析技术。此外，细胞反应 对冰毒和谷氨酸诱导的神经毒性将通过测量 血影蛋白的分解、羟基自由基的形成和脂质过氧化。 第一系列实验将评估是否改变了 细胞外谷氨酸浓度影响冰毒诱导的纹状体 多巴胺耗竭。第二个具体目标将是扰乱 损毁腹侧皮质纹状体谷氨酸能传递 丘脑核团。这些损伤对冰毒诱导的大鼠心脏功能的影响 纹状体胞外谷氨酸浓度及其长期效应 纹状体多巴胺含量和酪氨酸羟化酶免疫反应性的研究 将会被确定。第三和第四个具体目标将决定 胞外浓度增加的细胞毒性后果 多巴胺和谷氨酸通过测量幽灵蛋白的水解度， 羟基自由基的产生及其伴随的神经毒性 作用表现为脂质过氧化反应。最终目标将是评估 反复应激事件的影响和 反复服用小剂量冰毒或皮质酮 冰毒对前脑多巴胺神经元的后续神经毒性作用 地区。总体而言，这些实验具有重要的临床意义 意味着有毒的兴奋性氨基酸的影响， 作为决定因素的环境应激源和/或先前的药物暴露 药物引起的神经毒性的后果。因为压力有很强的 对自我给药苯丙胺敏感性的影响，这些 研究也与先前暴露在空气中的后果有关 冰毒的神经毒性剂量对寻求毒品行为和对 压力很大的事件。

Methamphetamine (METH) is a drug of abuse with pronounced effects on the CNS including psychomotor activation and mood elevation. These effects have contributed to its high abuse liability. Furthermore, prolonged used has produced a behavioral pattern resembling paranoid schizophrenia. These behavioral side effects and abuse potential suggest that METH produces long-lasting neurotoxic effects in the CNS. However, the exact mechanisms by which METH damages dopamine neurons are unknown. Excitatory amino acids such as glutamate have been implicated in the METH-induced depletions of dopamine. The primary objective of this proposal is to elucidate the factors underlying METH toxicity and focuses on the glutamate-dependent mechanisms and responses mediating the toxic effects of METH to striatal dopamine neurons. Pharmacological manipulations of glutamate transmission and in vivo measures of extracellular concentrations of dopamine and glutamate using microdialysis will be employed. In addition, the cellular responses to METH and glutamate-induced neurotoxicity will be assessed by measuring spectrin breakdown, hydroxyl radical formation, and lipid peroxidation. The first series of experiments will evaluate whether alterations in extracellular glutamate concentrations affect METH-induced striatal dopamine depletIons. The second specific aim will be to disrupt corticostriatal glutamatergic transmission by lesioning the ventral thalamic nuclei. The effects of these lesions on METH induced increases in striatal extra cellular glutamate concentrations and its long term effects on striatal dopamine content and tyrosine hydroxylase immunoreactivity will be determined. The third and fourth specific aims will determine the cytotoxic consequences of the increased extracellular concentrations of dopamine and glutamate by measuring the degree of spectrin proteolysis, the production of hydroxyl free radicals and their attendant neurotoxic effects indicated by lipid peroxidation. The final aim will be to evaluate the effects of repeated stress episodes and repeated administrations of low doses of METH or corticosterone on the subsequent neurotoxic effects of METH to dopamine neurons in forebrain regions. Overall, these experiments have significant clinical implications for the influence of toxic excitatory amino acids, environmental stressors, and/or prior drug exposure as determinants and consequences of drug-induced neurotoxicity. Since stress has a strong influence on the susceptibility to self administer amphetamine, these studies are also relevant to the consequences of prior exposure to neurotoxic doses of METH on drug seeking behavior and the reactivity to stressful events.