Effects of Stress and Glutamatergic Agents on Glutamate Cycling and Behavior
应激和谷氨酸药物对谷氨酸循环和行为的影响
基本信息
- 批准号:7741163
- 负责人:
- 金额:$ 34.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-10 至 2014-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcetatesAcidsAcuteAmino Acid NeurotransmittersAmino AcidsAmygdaloid structureAnhedoniaAnimal ModelAnimalsAntidepressive AgentsAstrocytesAttenuatedBehaviorBehavioralBehavioral ModelBehavioral ParadigmBiological AssayBrain regionCeftriaxoneCell CountCell physiologyCharacteristicsChronicChronic stressClinicalControl AnimalDataDevelopmentDiagnosisDiseaseDoseDrug usageExhibitsExposure toFDA approvedFunctional disorderGene ProteinsGeneticGenetic ModelsGlial Fibrillary Acidic ProteinGlucoseGlutamate Metabolism PathwayGlutamate TransporterGlutamatergic AgentsGlutamatesGlutamineGoalsHigh Pressure Liquid ChromatographyHippocampus (Brain)In Situ HybridizationIndividualInfusion proceduresInterventionKnockout MiceKnowledgeLabelLaboratoriesLactamsLiteratureMajor Depressive DisorderMass Spectrum AnalysisMeasuresMediatingMental disordersMetabolismMicrodialysisModelingMood DisordersMoodsMusNational Institute of Mental HealthNeurogliaNeuronsNeurotransmittersPatientsPharmaceutical PreparationsPhenotypePhysiologicalPrefrontal CortexPropertyProteinsPublic HealthRattusRegulationReportingResearchRiluzoleRodentRodent ModelRoleSalineSamplingSeriesSignal TransductionSpecificityStressSucroseSynapsesSystemTestingTherapeuticTimeWestern BlottingWorkacute stressbasebehavior testdensitydepressiondepressive symptomsdihydrokainatedrug developmentextracellulargamma-Aminobutyric Acidimprovedin vivoinhibitor/antagonistmouse modelneurotransmissionnovelpreclinical studypreferencepreventpublic health relevanceresponsestress related disorderstressortandem mass spectrometrytransport inhibitoruptake
项目摘要
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.
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)之间存在密切关系。压力和谷氨酸能信号之间的关系是通过发现应激暴露后几个脑区细胞外谷氨酸(Glu)浓度升高来说明的。最近的一系列研究表明,几类谷氨酸调节剂在动物模型中具有抗抑郁药样特性,以及在情绪障碍患者中,从而为谷氨酸神经传递和MDD之间的联系提供了额外的支持。基于诊断为MDD的个体中GABA和Glu浓度异常的发现,以及越来越多的文献记录了与MDD相关的胶质细胞数量和密度的显著减少,我们提出了一种模型,即星形胶质细胞功能受损和谷氨酸/谷氨酰胺循环中断在MDD的病理生理学中起着核心作用。阿曲唑是FDA批准的用于延迟ALS进展的Glu调节剂,其通过调节神经元Glu释放和增强Glu摄取而表现出抗谷氨酸能特性。一些研究现在也表明利鲁唑在MDD患者中的治疗作用。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表明,利鲁唑减弱和逆转几种啮齿动物模型中的行为应激的影响,这些模型通常用于测试抗抑郁药物活性。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循环速率增加,并减弱应激对星形胶质细胞功能的影响。为了进一步检验增强的Glu摄取可以预防或减弱应激的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,在用于评估抗抑郁样活性的几种啮齿动物模型中检查了头孢曲松的影响,头孢曲松是一种2-内酰胺,导致Glu转运蛋白GLT 1表达增加和Glu摄取增加。研究表明,头孢曲松具有与抗抑郁药一致的特征。我们现在想研究慢性应激和Glu调节药物对Glu循环、细胞外Glu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。我们还将专门探讨GLT 1介导的Glu摄取在应激中的作用,以及使用谷氨酸摄取的药理学抑制剂和小鼠GLT 1功能受损的遗传模型来研究这些药物的机制。这些研究的结果可以大大扩展我们对精神疾病的生理反应的理解。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。这些治疗的局限性可能与以下事实有关:它们主要是通过serindipity发现的,而不是通过真正理解疾病本身的病理生理机制。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,也有助于在对精神疾病的病理生理学有更多了解的基础上,寻求开发新的更好的精神疾病干预措施。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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GERARD SANACORA其他文献
GERARD SANACORA的其他文献
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{{ truncateString('GERARD SANACORA', 18)}}的其他基金
1/3-Efficacy and Tolerability of Riluzole in Treatment-Resistant Depression
1/3-利鲁唑治疗难治性抑郁症的疗效和耐受性
- 批准号:
8269777 - 财政年份:2010
- 资助金额:
$ 34.31万 - 项目类别:
1/3-Efficacy and Tolerability of Riluzole in Treatment-Resistant Depression
1/3-利鲁唑治疗难治性抑郁症的疗效和耐受性
- 批准号:
7887134 - 财政年份:2010
- 资助金额:
$ 34.31万 - 项目类别:
1/3-Efficacy and Tolerability of Riluzole in Treatment-Resistant Depression
1/3-利鲁唑治疗难治性抑郁症的疗效和耐受性
- 批准号:
8463247 - 财政年份:2010
- 资助金额:
$ 34.31万 - 项目类别:
1/3-Efficacy and Tolerability of Riluzole in Treatment-Resistant Depression
1/3-利鲁唑治疗难治性抑郁症的疗效和耐受性
- 批准号:
8472638 - 财政年份:2010
- 资助金额:
$ 34.31万 - 项目类别:
1/3-Efficacy and Tolerability of Riluzole in Treatment-Resistant Depression
1/3-利鲁唑治疗难治性抑郁症的疗效和耐受性
- 批准号:
8114117 - 财政年份:2010
- 资助金额:
$ 34.31万 - 项目类别:
Effects of Stress and Glutamatergic Agents on Glutamate Cycling and Behavior
应激和谷氨酸药物对谷氨酸循环和行为的影响
- 批准号:
8068822 - 财政年份:2009
- 资助金额:
$ 34.31万 - 项目类别:
Effects of Stress and Glutamatergic Agents on Glutamate Cycling and Behavior
应激和谷氨酸药物对谷氨酸循环和行为的影响
- 批准号:
8454517 - 财政年份:2009
- 资助金额:
$ 34.31万 - 项目类别:
13C Measurement of GABA Synthesis in Depression
抑郁症中 GABA 合成的 13C 测量
- 批准号:
7871062 - 财政年份:2009
- 资助金额:
$ 34.31万 - 项目类别:
Effects of Stress and Glutamatergic Agents on Glutamate Cycling and Behavior
应激和谷氨酸药物对谷氨酸循环和行为的影响
- 批准号:
8259232 - 财政年份:2009
- 资助金额:
$ 34.31万 - 项目类别:
Effects of Stress and Glutamatergic Agents on Glutamate Cycling and Behavior
应激和谷氨酸药物对谷氨酸循环和行为的影响
- 批准号:
7891351 - 财政年份:2009
- 资助金额:
$ 34.31万 - 项目类别:
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