Effects of Stress and Glutamatergic Agents on Glutamate Cycling and Behavior

6.项目总结/摘要 越来越多的证据表明，紧张，氨基酸神经递质系统之间存在着密切的关系， 重度抑郁症（MDD）压力和神经递质信号之间的关系是 通过在几个脑区发现细胞外谷氨酸（Glu）浓度升高来说明 在压力暴露之后。最近的一系列研究表明，几类谷氨酸调节蛋白， 药物在动物模型中，以及在情绪障碍患者中， 从而为Glu神经传递和MDD之间的联系提供了额外的支持。基于 在诊断为MDD的个体中发现异常的GABA和Glu浓度， 文献记录了与MDD相关的神经胶质细胞数量和密度的显著减少，我们 提出了一种模型，即受损的星形胶质细胞功能和谷氨酸/谷氨酰胺循环的破坏， 在MDD的病理生理学中起核心作用。阿舒唑，FDA批准的谷氨酸调节剂，用于延迟 ALS进展，通过调节神经元Glu的释放表现出抗谷氨酸能特性， 增强Glu摄取。一些研究现在也表明利鲁唑在以下患者中的治疗作用： MDD。与我们的假设模型一致，最近从我们的实验室收集的初步数据 证明利鲁唑在几种啮齿动物模型中减弱和逆转行为应激的作用， 通常用于测试抗抑郁药物的活性。此外，我们小组的其他工作使用13 C- MRS测量Glu，谷氨酰胺（Gln）和GABA合成的速率，表明慢性应激降低了 星形胶质细胞代谢和Glu/Gln和GABA/Gln循环。阿曲唑给药导致 Glu/Gln循环，并减弱应激对星形胶质细胞功能的影响。为了进一步验证假设， 增强的Glu摄取可以预防或减轻应激的影响，并具有抗抑郁样活性，我们 最近完成了一项研究，检查头孢曲松的影响，一种内酰胺，导致增加 Glu转运蛋白GLT 1的表达和Glu摄取增加，在几种用于评估 抗抑郁活性。研究表明，头孢曲松的特征与 抗抑郁药我们现在要研究慢性压力和调节血糖的药物的作用 谷氨酸循环，细胞外谷氨酸含量，以及这些影响之间的关系， 神经传递和抑郁症的动物模型。我们还将具体探讨GLT 1的作用 介导的Glu摄取的压力和这些药物的机制，使用药理学抑制剂， 小鼠谷氨酸摄取和GLT 1功能受损的遗传模型。这些研究的结果可以 显著地扩展了我们对压力的生理反应与精神疾病的理解。 此外，这些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.