Stress, depression and effects of novel antidepressants on excitatory synapses
压力、抑郁和新型抗抑郁药对兴奋性突触的影响
基本信息
- 批准号:9270600
- 负责人:
- 金额:$ 38.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-05-15 至 2020-04-30
- 项目状态:已结题
- 来源:
- 关键词:Adverse effectsAffectAgonistAnestheticsAnimalsAntidepressive AgentsAnxietyAppetitive BehaviorBehaviorBehavioralBehavioral AssayBenzodiazepine ReceptorBenzodiazepinesBindingBinding SitesBiochemicalBiological AssayBrainCannulationsCellsChemosensitizationChronicChronic stressDataDepressed moodDisinhibitionDoseDown SyndromeDrug IndustryElectrophysiology (science)EtiologyExcitatory SynapseExhibitsFoodFunctional disorderGene ExpressionGrantHippocampus (Brain)HourHumanImpairmentIndividualInjection of therapeutic agentInstinctInterneuronsKetamineLong-Term PotentiationMeasuresMediatingMental DepressionModelingMolecularMorbidity - disease rateMusNational Institute of Mental HealthNatureNeuronsNucleus AccumbensOutcomePathologicPatientsPharmaceutical PreparationsPhasePhase I Clinical TrialsPropertyProsencephalonPyramidal CellsRattusResearch Domain CriteriaRewardsRodentSeizuresSelective Serotonin Reuptake InhibitorSignal PathwaySignaling ProteinSiteSocial DominanceSocial InteractionStressSucroseSynapsesSynaptic TransmissionSynaptic plasticityTestingTherapeuticTherapeutic EffectWorkbasebehavioral impairmentbrain tissuecognitive enhancementdepressed patientimprovedin vivoinnovationmortalityneural circuitneuronal circuitrynovelnovel drug classoptogeneticspreferencepublic health relevancereceptorreceptor functionresponserestorationsex
项目摘要
DESCRIPTION (provided by applicant): Depression is a major cause of mortality and morbidity worldwide. Its etiology is unknown. Current therapeutic treatments are effective in only half of patients and, when effective, work slowly. There is increasing evidence that a weakening of excitatory synaptic transmission between cells in multiple cortico-mesolimbic reward circuits is induced in rodents by chronic stress, perhaps underlying the wide range of behaviors affected by stress. Innovation: We discovered in the previous grant cycle that selective serotonin reuptake inhibitors act slowly to restore this weakened synaptic excitation. Based on the rapid antidepressant actions of ketamine, we identified a novel class of compounds that we predict will act rapidly to strengthen pathologically weakened excitatory synapses and can thus be predicted to exert a fast acting antidepressant action with fewer side effects than ketamine. Specifically, we will test the hypotheses that Partial inverse agonists of the benzodiazepine binding site of GABAA receptors containing a5 subunits (PIAGRA) will produce a rapid and persistent restoration of a range of behaviors that are affected by chronic stress paradigms in rats and mice and that they will restore the strength of pathologically weakened excitatory synapses, as measured in electrophysiological and biochemical assays. Approach: Our preliminary data show that a unique PIAGRA compound (L-655,078) restores normal sucrose preference and social interaction within 24hrs in rats subjected to two chronic stress paradigms and restores the strength of AMPAR-mediated synaptic excitation and GluA1 expression in hippocampal synapses in rats subjected to chronic stress. We also observed that synapses formed by hippocampal projections to neurons in the nucleus accumbens display activity-dependent long-term potentiation. We propose to test the following specific aims. 1: Determine the persistence and generality of PIAGRA's antidepressant actions on a range of appetitive and innate behaviors (food, social interactions, sex). 2: Determine the mechanism of action of PIAGRA at the level of synaptic circuits. 3: Determine the effects of stress and PIAGRA on hippocampal-NAc excitatory synapses. We will use multiple chronic stress paradigms to produce changes in reward behavior, then test whether PIAGRA compounds produce rapid (<24 hrs) and persistent normalization of these behaviors and determine how long these beneficial actions persist. We will then use electrophysiological recording to test the strength of
excitatory interactions, along with several biochemical and molecular correlates, in brain tissue taken from these animals 24 hrs after injection of the compounds. Outcome: Our study will provide a thorough proof-of-concept test of a novel class of AD compounds at several levels of analysis from behavior to molecules, as encouraged by the NIMH's Research Domain Criteria initiative. Evidence of a beneficial therapeutic action in rodents after chronic stress, and the identification of key circuits at which they act, will encourage a test of their therapeutic effect in depressed patients.
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
SCOTT M. THOMPSON其他文献
SCOTT M. THOMPSON的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('SCOTT M. THOMPSON', 18)}}的其他基金
Central Pain Syndrome: Thalamic Hyperexcitability After Denervation?
中枢性疼痛综合征:去神经后丘脑过度兴奋?
- 批准号:
7369672 - 财政年份:2007
- 资助金额:
$ 38.18万 - 项目类别:
Central Pain Syndrome: Thalamic Hyperexcitability After Denervation?
中枢性疼痛综合征:去神经后丘脑过度兴奋?
- 批准号:
7254559 - 财政年份:2007
- 资助金额:
$ 38.18万 - 项目类别:
Pre and Postsynaptic Consequences of Traumatic CNS Injury
中枢神经系统损伤的突触前和突触后后果
- 批准号:
7991811 - 财政年份:2002
- 资助金额:
$ 38.18万 - 项目类别:
Axonal Sprouting and Epilepsy after Traumatic CNS Injury
中枢神经系统外伤后的轴突出芽和癫痫
- 批准号:
6875711 - 财政年份:2002
- 资助金额:
$ 38.18万 - 项目类别:
Pre and Postsynaptic Consequences of Traumatic CNS Injury
中枢神经系统损伤的突触前和突触后后果
- 批准号:
7383287 - 财政年份:2002
- 资助金额:
$ 38.18万 - 项目类别:
Axonal Sprouting and Epilepsy after Traumatic CNS Injury
中枢神经系统外伤后的轴突出芽和癫痫
- 批准号:
6624509 - 财政年份:2002
- 资助金额:
$ 38.18万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 38.18万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 38.18万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 38.18万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 38.18万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 38.18万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 38.18万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 38.18万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 38.18万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 38.18万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 38.18万 - 项目类别:
Studentship