Effects of Stress and Glutamatergic Agents on Glutamate Cycling and Behavior

6.项目摘要/摘要 越来越多的证据表明，应激、氨基酸神经递质系统之间存在着密切的关系 和严重抑郁障碍(MDD)。应激和谷氨酸能信号之间的关系是 在几个大脑区域发现细胞外谷氨酸(Glu)浓度升高就是例证 在压力暴露之后。最近的一系列研究表明，几类谷氨酸调节 在动物模型中，以及在情绪障碍患者中，药物具有抗抑郁剂样的特性， 从而为谷氨酸神经递质与MDD之间的联系提供了额外的支持。基于 诊断为MDD和生长的MDD患者的GABA和Glu浓度异常的结果 文献记录了与MDD相关的神经胶质细胞数量和密度显著减少，我们有 提出了一种星形胶质细胞功能受损和谷氨酸/谷氨酰胺循环服务中断的模型 在MDD的病理生理学中起核心作用。利鲁唑，一种FDA批准的葡萄糖调节剂，用于延迟 肌萎缩侧索硬化症进展，通过调节神经元谷氨酸释放和 增强谷氨酸摄取。一些研究现在也提示利鲁唑对慢性阻塞性肺疾病患者有治疗作用。 MDD。与我们的假设模型一致，最近从我们的实验室收集了初步数据 证明利鲁唑在几种啮齿动物模型上减弱和逆转行为应激的影响 通常用于测试抗抑郁药物的活性。此外，我们小组使用13C的其他工作- MRS测量谷氨酸、谷氨酰胺(Gln)和GABA合成的比率，表明慢性应激会减少 星形胶质细胞代谢与Glu/Gln和GABA/Gln循环。利鲁唑的使用可增加患者的死亡率。 Glu/Gln循环并减弱应激对星形胶质细胞功能的影响。为了进一步检验这个假设 增强的谷氨酸摄取可以防止或减弱压力的影响，并具有抗抑郁活性，我们 最近完成了一项研究，考察了头孢曲松的作用，头孢曲松是一种内酰胺类药物，可导致 在几种用于评估的啮齿动物模型中，谷氨酸转运体GLT1的表达和谷氨酸摄取增加 抗抑郁药样活动。研究表明，头孢曲松的轮廓与 抗抑郁剂。我们现在想研究一下慢性压力和葡萄糖调节药物的影响。 谷氨酸循环、胞外谷氨酸含量及其对谷氨酸能的影响 神经传递和抑郁症的动物模型。我们还将专门探讨GLT1的作用 应激中介导的谷氨酸摄取及其药物的作用机制 谷氨酸摄取与小鼠GLT1功能受损的遗传模型。这些研究的结果可能 大大扩展了我们对压力的生理反应与精神疾病之间的关系的理解。 此外，研究结果可能为我们提供抗抑郁药物的新靶点。 发展。

6. PROJECT SUMMARY/ABSTRACT Increasing evidence suggests a tight relationship exists between stress, amino acid neurotransmitter systems and Major Depressive Disorder (MDD). The relationship between stress and glutamatergic signaling is illustrated by the finding of elevated extracellular glutamate (Glu) concentrations in several brain regions following stress exposure. A recent series of studies demonstrate that several classes of Glu-modulating agents possess antidepressant-like properties in animal models, as well as in patients with mood disorders, thus providing additional support for the connection between Glu neurotransmission and MDD. Based on findings of abnormal GABA and Glu concentrations in individuals diagnosed with MDD, and a growing literature documenting significant reductions in the glial cell number and density associated with MDD, we have proposed a model whereby impaired astrocyte function and a disruption of glutamate/glutamine cycling serves a central role in the pathophysiology of MDD. Riluzole, an FDA-approved Glu-modulating agent used to delay ALS progression, exhibits anti-glutamatergic properties via modulation of neuronal Glu release and enhancement of Glu uptake. Several studies now also suggest a therapeutic action of riluzole in patients with MDD. Consistent with our hypothesized model, recently collected preliminary data from our laboratory demonstrate that riluzole attenuates and reverses the effects of behavioral stress in several rodent models that are commonly used to test for antidepressant drug activity. In addition, other work from our group using 13C- MRS to measure the rate of Glu, glutamine (Gln), and GABA synthesis, suggests that chronic stress reduces astrocyte metabolism and Glu/Gln and GABA/Gln cycling. Riluzole admnistration resulted in increased rates of Glu/Gln cycling and attenuates the effects of stress on astrocyte function. To further test the hypothesis that enhanced Glu uptake could prevent or attenuate the effects of stress and have antidepressant-like activity, we recently completed a study examining the effects of ceftriaxone, a ¿-lactam that results in increased expression of the Glu transporter GLT1 and increased Glu uptake, in several rodent models used to assess antidepressant-like activity. The studies demonstrated that ceftriaxone has a profile consistent with antidepressant agents. We would now like to examine the effects of chronic stress and Glu-modulating drugs on Glu cycling, extracellular Glu content, and the relationship between these effects on glutamatergic neurotransmission and animal models of depression. We will also specifically explore the role of GLT1 mediated Glu uptake in stress and the mechanism of these drugs using pharmacological inhibitors of glutamate uptake and a genetic model of impaired GLT1 function in mice. The results of these studies could significantly expand our understanding relating the physiological response to stress to mental illness. Moreover, the results of the studies could potentially provide us with novel targets for antidepressant drug development.