METHAMPHETAMINE TOXICITY AND CORTICOSTRIATAL GLUTAMATE

甲基苯丙胺(MA)是一种滥用药物，对 中枢神经系统包括精神运动刺激和情绪提升。这些影响 都导致了其高度的滥用责任。此外，延长了 使用产生了一种类似于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，MA 在中枢神经系统产生持久的神经毒性作用。最近的研究表明 涉及兴奋性氨基酸参与MA诱导的耗竭 纹状体多巴胺(DA)和5-羟色胺(5-羟色胺)。到目前为止还没有研究 然而，已经直接测量了大脑兴奋性氨基酸，如 反复MA过程中的兴奋性毒素谷氨酸 行政管理。MA选择性地破坏DA和5HT的方式 虽然已经提出了多巴胺能机制，但神经元尚不清楚。 这项建议将研究潜在的皮质-皮质下机制 促进皮质纹状体谷氨酸释放和NMDA受体激活 在MA管理部门之后。这些研究的主要目标是 目的：探讨MA对多巴胺和5-羟色胺神经元的神经毒性作用。 纹状体中的谷氨酸是部分由谷氨酸调节的。据推测， 反复注射MA的纹状体神经毒性部分是由于 纹状体谷氨酸释放的累积增加通过增加 皮质纹状体谷氨酸能传递。体内微透析会 用于同时测量细胞外谷氨酸和 觉醒行为患者纹状体和额叶皮质中的生物胺 大鼠反复全身给药和皮质内给药 妈。测定纹状体组织中DA和5-羟色胺的含量 以MA治疗终止后作为毒性指标。系统性 并将使用特定NMDA受体拮抗剂的局部灌流 为了确定NMDA受体和大脑的作用 参与MA致纹状体改变的区域(S) 谷氨酸释放和神经毒性。大鼠的调节作用 肾上腺糖皮质激素、皮质酮也将接受有关检查 MA增加胞外谷氨酸的机制。它 希望从这些实验中获得的具体信息将 提供对神经机制的基本洞察力 对MA和其他精神刺激药物的神经毒性。

Methamphetamine (MA) is a drug of abuse with pronounced effects on the CNS including psychomotor stimulation and mood elevation. These effects have contributed to its high abuse liability. Furthermore, prolonged use has produced a behavioral pattern resembling paranoid schizophrenia. These behavioral side effects and abuse potential suggest that MA produces long-lasting neurotoxic effects in the CNS. Recent studies have implicated an excitatory amino acid involvement in MA-induced depletions of striatal dopamine (DA) and serotonin (5HT). No studies to date however, have directly measured brain excitatory amino acids such as the excitotoxin, glutamate, during the time course of repeated MA administration. The manner in which MA selectively destroys DA and 5HT neurons is unknown although a dopaminergic mechanism has been proposed. This proposal will examine a potential cortical-subcortical mechanism of enhanced corticostriatal glutamate release and NMDA receptor activation following MA administration. The primary objective of these studies will be to establish that the neurotoxic effects of MA on DA and 5HT neurons in striatum are mediated in part by glutamate. It is posited that the striatal neurotoxicity to repeated MA injections is partially due to a cumulative increase in striatal glutamate release via increased corticostriatal glutamatergic transmission. In vivo microdialysis will be used to simultaneously measure extracellular levels of glutamate and biogenic amines in both the striatum and frontal cortex of awake-behaving rats during the repeated systemic and intracortical administrations of MA. Striatal tissue content of DA and 5HT will be measured one week after the termination of MA treatment as an index of toxicity. Systemic and local perfusions of specific NMDA receptor antagonists will be used to determine the contribution of the NMDA receptor and the brain region(s) involved in mediating the MA-induced changes in striatal glutamate release and neurotoxicity. The modulatory role of the rat adrenal glucocorticoid, corticosterone will also be examined with regard to the mechanism through which MA increases extracellular glutamate. It is hoped that specific information derived from these experiments will provide basic insight into the neural mechanisms responsible for the neurotoxicity to MA and other psychostimulant drugs.