Effects of Stress and Glutamatergic Agents on Glutamate Cycling and Behavior

描述（由申请人提供）：越来越多的证据表明，压力、氨基酸神经递质系统和重度抑郁症（MDD）之间存在密切的关系。应激与谷氨酸信号传导之间的关系通过发现应激暴露后大脑几个区域的细胞外谷氨酸（Glu）浓度升高来说明。最近的一系列研究表明，在动物模型和情绪障碍患者中，几种Glu调节剂具有抗抑郁样特性，从而为Glu神经传递和重度抑郁症之间的联系提供了额外的支持。基于在被诊断为重度抑郁症的个体中发现的异常GABA和Glu浓度，以及越来越多的文献记录了与重度抑郁症相关的神经胶质细胞数量和密度的显著减少，我们提出了一个模型，即星形胶质细胞功能受损和谷氨酸/谷氨酰胺循环中断在重度抑郁症的病理生理中起着核心作用。利鲁唑是一种fda批准的用于延缓ALS进展的谷氨酸调节剂，通过调节神经元谷氨酸释放和增强谷氨酸摄取来表现出抗谷氨酸能特性。现在有几项研究也表明利鲁唑对重度抑郁症患者有治疗作用。与我们的假设模型一致，最近从我们实验室收集的初步数据表明，利鲁唑可以减轻和逆转几种啮齿动物模型中行为压力的影响，这些模型通常用于测试抗抑郁药物的活性。此外，我们小组使用13C- MRS测量Glu，谷氨酰胺（Gln）和GABA合成速率的其他工作表明，慢性应激降低星形胶质细胞代谢和Glu/Gln和GABA/Gln循环。利鲁唑可增加Glu/Gln循环速率，并减弱应激对星形胶质细胞功能的影响。为了进一步验证增强谷氨酸摄取可以预防或减轻应激影响并具有抗抑郁样活性的假设，我们最近完成了一项研究，在几种用于评估抗抑郁样活性的啮齿动物模型中，研究了头孢曲松的作用。头孢曲松是一种2-内酰胺，可导致谷氨酸转运蛋白GLT1表达增加和谷氨酸摄取增加。研究表明，头孢曲松具有与抗抑郁药物一致的特征。我们现在想研究慢性应激和谷氨酸调节药物对谷氨酸循环、细胞外谷氨酸含量的影响，以及这些对谷氨酸能神经传递的影响与抑郁症动物模型之间的关系。我们还将利用谷氨酸摄取的药理学抑制剂和小鼠GLT1功能受损的遗传模型，专门探讨GLT1介导的谷氨酸摄取在应激中的作用以及这些药物的机制。这些研究结果可以显著地扩展我们对精神疾病的生理应激反应的理解。此外，研究结果可能为我们提供抗抑郁药物开发的新靶点。公共卫生相关性：最近的研究强调了我们目前抗抑郁药物的局限性。这些治疗方法的局限性可能与以下事实有关：它们主要是通过偶然发现的，而不是通过对疾病本身的病理生理机制的真正理解。本提案中概述的研究与公共卫生直接相关，并与NIMH主任的战略计划相一致，既有助于识别和更好地了解精神障碍的原因，又有助于在对精神疾病病理生理学的进一步了解的基础上，寻求开发新的更好的精神疾病干预措施。

DESCRIPTION (provided by applicant): 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 2-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. PUBLIC HEALTH RELEVANCE: Recent studies have highlighted the limitations of our current armamentarium of antidepressant medications. The limitations of these treatments are likely to be related to the fact that they were discovered largely through serindipity, and not through a true understanding of the pathophysiological mechanisms underlying the disorders themselves. The research outlined in this proposal has direct relevance to public health and is consistent with the NIMH Director's Stategic plan by both helping to identify and better understand the causes of mental disorders, as well as seeking to develope new and better interventions for psychiatric illnesess based on the increased understanding of the pathophysiology of the disorders.