Contributions of Glial Glutamate Transport and Transmission to Drug Abuse
Contributions of Glial Glutamate Transport and Transmission to Drug Abuse
批准号:
8656833
负责人:
Kathryn Joanna Reissner
金额:
$24.9万
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
已结题
起止时间:
2013-08-01 至 2016-07-31
关键词:
AbstinenceAcetylcysteineAcuteAffectAffinityAwardBathingBehaviorBehavioralCatalytic DomainCeftriaxoneCellsChemosensitizationChronicClinicalCocaineCommunicationCuesCystineDataDrug abuseElectrophysiology (science)EquilibriumExtinction (Psychology)FrequenciesGlutamate TransporterGlutamatesGoalsGrantHealthHomeostasisIn VitroInjection of therapeutic agentInvestigationMeasurementMeasuresMediator of activation proteinMentorsMetabotropic Glutamate ReceptorsMicrodialysisMicroinjectionsModelingMonitorN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNeurogliaNeuronsNucleus AccumbensPathologyPharmaceutical PreparationsPharmacotherapyPhasePhysiologicalProcessPropertyQuality of lifeRattusReceptor ActivationRelapseRelative (related person)RoleSalineSelf AdministrationSliceSynapsesSynaptic TransmissionSynaptic plasticitySystemTechniquesTestingTherapeuticTherapeutic EffectTherapeutic InterventionTrainingaddictioncandidate identificationcocaine exposuredesigndrug of abusedrug relapseextracellulargenetic manipulationin vivoinhibitor/antagonistneuroadaptationpatch clampprotein expressionreceptorresearch studyrestorationtransmission processuptake
中文摘要
胶质细胞谷氨酸转运和传递在药物滥用中的作用
成瘾的最隐蔽的临床特征之一是在长期服用后复发的脆弱性
禁欲现有证据表明,细胞核内谷氨酸稳态的破坏
抑郁症是这种慢性复发脆弱性的一种促成机制。谷氨酸稳态是指
突触外和突触神经元谷氨酸浓度之间的平衡,调节突触
可塑性在长期接触可卡因后发生的长期神经适应中,
胱氨酸-谷氨酸交换器(xCT)催化亚基的功能和蛋白表达降低
和高亲和力神经胶质谷氨酸转运蛋白GLT-1,两个非突触细胞外
谷氨酸盐。因此,在服用可卡因后,
延髓核内的自我给药。使用N-乙酰半胱氨酸(NAC)或
头孢曲松削弱可卡因的恢复并增加GLT-1和xCT的表达。[As一种手段
更全面地了解负责谷氨酸持续中断的变稳态机制,
稳态和它们对成瘾的贡献,我采用了反义敲除策略,
确定GLT-1和xCT在大鼠成瘾恢复模型中的相对贡献。初步
数据表明,胶质细胞GLT-1的表达,而不是xCT,是治疗效果的关键介质,
NAC。因此,本研究的目的是检验可卡因暴露后神经胶质细胞的适应性这一假设,
影响谷氨酸的释放和摄取,进而影响谷氨酸和谷氨酸受体的稳态平衡。
可卡因诱导的细胞和突触神经适应性。这将在指导期间完成
使用(i)体内微透析来测量遗传后的谷氨酸浓度
GLT-1的操作,和(ii)膜片钳电生理学,以比较培养基的生理特性
棘神经元(mEPSC,AMPA:NMDA比率,[胶质细胞衍生的慢内向电流])在这些相同的条件下,
条件为该奖项的独立阶段提出的实验将继续进行这些研究
并研究(iii)在这些过程中代谢型谷氨酸受体的参与。
英文摘要
Contributions of glial glutamate transport and transmission to drug abuse
One of the most insidious clinical features of addiction is the vulnerability to relapse following extended
abstinence. Existing evidence suggests that a disruption in glutamate homeostasis within the nucleus
accumbens is a contributing mechanism to this chronic relapse vulnerability. Glutamate homeostasis refers to
the balance between extrasynaptic and synaptic neuronal glutamate concentrations that regulate synaptic
plasticity. Among the long-lasting neuroadaptations which occur following chronic exposure to cocaine are
decreased function and protein expression of the catalytic subunit of the cystine-glutamate exchanger (xCT)
and high affinity glial glutamate transporter GLT-1, two integral regulators of nonsynaptic extracellular
glutamate. Accordingly, decreased extracellular glutamate concentrations are measured following cocaine
self-administration in the nucleus accumbens. Systemic treatment with either N-acetylcysteine (NAC) or
ceftriaxone impairs reinstatement to cocaine and increases expression of both GLT-1 and xCT. [As a means
of understanding more fully the allostatic mechanisms responsible for enduring disruptions of glutamate
homeostasis and their contribution to addiction, I have employed an antisense knockdown strategy to
determine the relative contributions of GLT-1 and xCT in a rat reinstatement model of addiction. Preliminary
data indicate that expression of glial GLT-1, but not xCT, is the critical mediator of the therapeutic effect of
NAC. Thus, a goal of this proposal is to test the hypothesis that adaptations in glia following cocaine exposure
influence the release and uptake of glutamate, in turn affecting the homeostatic balance of glutamate and the
cellular and synaptic neuroadaptations induced by cocaine.] This will be accomplished during the mentored
phase of the award using (i) in vivo microdialysis to measure glutamate concentrations following genetic
manipulation of GLT-1, and (ii) patch clamp electrophysiology to compare physiological properties of medium
spiny neurons (mEPSCs, AMPA:NMDA ratios, [glial-derived slow inward currents]) under these same
conditions. Experiments proposed for the independent phase of the award will go on to continue these studies
and investigate (iii) the engagement of metabotropic glutamate receptors in these processes.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Functional consequences of cocaine self-administration on astrocytes
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批准号:10682221
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项目类别:
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资助金额:$34.3万
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财政年份:2023
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负责人:Kathryn Joanna Reissner
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依托单位:
Novel cellular markers of drug-mediated calcium signaling in astrocytes
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批准号:10368128
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项目类别:
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资助金额:$18.72万
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财政年份:2021
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负责人:Kathryn Joanna Reissner
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依托单位:
Astrocyte-mediated mechanisms of cocaine seeking
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批准号:9293285
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项目类别:
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资助金额:$33.69万
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财政年份:2016
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负责人:Kathryn Joanna Reissner
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依托单位:
Astrocyte-mediated mechanisms of cocaine seeking
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批准号:9193717
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项目类别:
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资助金额:$32.11万
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财政年份:2016
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负责人:Kathryn Joanna Reissner
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依托单位:
Astrocyte-mediated mechanisms of cocaine seeking
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批准号:9902393
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项目类别:
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资助金额:$33.64万
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财政年份:2016
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负责人:Kathryn Joanna Reissner
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依托单位:
Contributions of Glial Glutamate Transport and Transmission to Drug Abuse
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批准号:9271420
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项目类别:
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资助金额:$1.42万
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财政年份:2013
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负责人:Kathryn Joanna Reissner
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依托单位:
Contributions of Glial Glutamate Transport and Transmission to Drug Abuse
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批准号:9059846
-
项目类别:
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资助金额:$1.37万
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财政年份:2013
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负责人:Kathryn Joanna Reissner
-
依托单位:
Contributions of Glial Glutamate Transport and Transmission to Drug Abuse
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批准号:8848449
-
项目类别:
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资助金额:$0.81万
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财政年份:2013
-
负责人:Kathryn Joanna Reissner
-
依托单位:
Contributions of Glial Glutamate Transport and Transmission to Drug Abuse
-
批准号:8708806
-
项目类别:
-
资助金额:$24.9万
-
财政年份:2013
-
负责人:Kathryn Joanna Reissner
-
依托单位:
Contributions of Glial Glutamate Transport and Transmission to Drug Abuse
-
批准号:8819276
-
项目类别:
-
资助金额:$7.3万
-
财政年份:2013
-
负责人:Kathryn Joanna Reissner
-
依托单位:
Contributions of Glial Glutamate Transport and Transmission to Drug Abuse
-
批准号:8300354
-
项目类别:
-
资助金额:$12.02万
-
财政年份:2012
-
负责人:Kathryn Joanna Reissner
-
依托单位:
Contributions of Glial Glutamate Transport and Transmission to Drug Abuse
-
批准号:8435395
-
项目类别:
-
资助金额:$12.02万
-
财政年份:2012
-
负责人:Kathryn Joanna Reissner
-
依托单位:
Cytoskeletal Mechanisms of Cocaine-Induced Neuroplasticity
-
批准号:8019051
-
项目类别:
-
资助金额:$5.47万
-
财政年份:2009
-
负责人:Kathryn Joanna Reissner
-
依托单位:
Cytoskeletal Mechanisms of Cocaine-Induced Neuroplasticity
-
批准号:7613183
-
项目类别:
-
资助金额:$5.01万
-
财政年份:2009
-
负责人:Kathryn Joanna Reissner
-
依托单位:
Cytoskeletal Mechanisms of Cocaine-Induced Neuroplasticity
-
批准号:7758749
-
项目类别:
-
资助金额:$5.22万
-
财政年份:2009
-
负责人:Kathryn Joanna Reissner
-
依托单位:
海外基金