Methamphetamine Toxicity and Corticostriatal Glutamate

描述（由申请人提供）：高剂量的甲基苯丙胺会产生神经毒性的长期后果，如人类认知缺陷和人类和动物多巴胺（DA）和5HT神经传递标志物的长期减少。我们在之前资助期间的研究和其他人的研究结果表明，高水平的纹状体谷氨酸（GLU）在冰毒毒性中起重要作用。然而，没有证据表明甲基苯丙胺如何增加纹状体GLU传递，以及这是否会产生兴奋性毒性损伤。此外，尽管甲基苯丙胺、环境压力和药物滥用在神经化学上有相似之处，但尚不清楚压力是否以及如何增强甲基苯丙胺的兴奋毒性作用。海马也容易受到甲基苯丙胺的毒性作用，由于该区域GLU神经元和糖皮质激素受体的密集组成，它对应激和兴奋性毒性损伤特别敏感。尽管大量研究表明海马体与认知有关，人类冰毒滥用者表现出认知缺陷，但令人惊讶的是，人们对冰毒如何损害海马体或压力如何影响冰毒的兴奋毒性作用知之甚少。该项目是我们先前研究的新延伸，将阐明glu介导的纹状体和海马兴奋毒性的神经化学决定因素和后果，以及它们如何受到先前暴露于慢性不可预测压力的影响。提出的具体目标将验证的首要假设是，纹状体中的兴奋毒性是由甲基安非他明产生的，通过先前暴露于慢性应激而增强，并由D1和D2受体不同地介导。兴奋性毒性与纹状体GLU突触前储存和细胞外浓度增加相平行，导致囊泡单胺转运蛋白（VMAT2）和线粒体电子传递链的氧化应激，最终导致蛋白酶体抑制和谱蛋白水解。此外，应激诱导的海马中GLU传递的增强同样可以通过突触和细胞外GLU的增加来证明，从而降低细胞生物能量，降低蛋白酶体激活和谱蛋白水解。

DESCRIPTION (provided by applicant): High doses of METH produce long-term consequences indicative of neurotoxicity as revealed by cognitive deficits in humans and long-term decreases in markers of dopamine (DA) and 5HT neurotransmission in humans and animals. Our studies during the previous funding period and findings by others revealed that high levels of striatal glutamate (GLU) play an important role in METH toxicity. Nevertheless, there is no evidence of how striatal GLU transmission is increased by METH and if this produces excitotoxic damage. Moreoever, despite the neurochemical similarities between METH, environmental stress, and drug abuse, it is unknown if and how stress might enhance the excitotoxic effects of METH. The hippocampus is also vulnerable to the toxic effects of METH and is particularly sensitive to stress and excitotoxic insult due the dense composition of GLU neurons and glucocorticoid receptors in this region. Despite numerous studies demonstrating that the hippocampus is involved in cognition and human METH abusers exhibit cognitive deficits, it is surprising that little is known about how METH damages the hippocampus or how stress affects the excitotoxic effects of METH. The proposed project is a novel extension of our prior studies and will elucidate the neurochemical determinants and consequences of GLU-mediated excitotoxicity to the striatum and hippocampus and how they are affected by prior exposure to chronic unpredictable stress. The overarching hypothesis that will be tested by the proposed specific aims is that excitotoxicity in the striatum is produced by METH, augmented by prior exposure to chronic stress, and mediated differentially by D1 and D2 receptors. Excitotoxicity will be paralleled by increased presynaptic storage and extracellular concentrations of striatal GLU resulting in oxidative stress to the vesicular monoamine transporter (VMAT2) and the mitochondrial electron transport chain to culminate in proteasomal inhibition and spectrin proteolysis. In addition, a stress-induced enhancement of GLU transmission in the hippocampus will be similarly evidenced by increased synaptic and extracellular GLU and consequently, decreased cellular bioenergetics, decreased proteasomal activation, and spectrin proteolysis.