Contributions of Glial Glutamate Transport and Transmission to Drug Abuse

胶质细胞谷氨酸转运和传播对药物滥用的贡献

• 批准号: 9271420
• 负责人: Kathryn Joanna Reissner
• 金额: $ 1.42万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271420
• 关键词: Abstinence; Acetylcysteine; Acute; Affect; Affinity; Award; Bathing; Behavior; Behavioral; Catalytic Domain; Ceftriaxone; Cells; Chemosensitization; Chronic; Clinical; Cocaine; Communication; Cues; Cystine; Data; Drug abuse; Electrophysiology (science); Equilibrium; Extinction (Psychology); Frequencies; Glutamate Transporter; Glutamates; Goals; Grant; Health; Homeostasis; In Vitro; Injection of therapeutic agent; Investigation; Measurement; Measures; Mediator of activation protein; Mentors; Metabotropic Glutamate Receptors; Microdialysis; Microinjections; Modeling; Monitor; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuroglia; Neurons; Nucleus Accumbens; Pathology; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physiological; Process; Property; Quality of life; Rattus; Receptor Activation; Relapse; Role; Saline; Self Administration; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Training; addiction; candidate identification; cocaine exposure; design; drug of abuse; drug relapse; extracellular; genetic manipulation; in vivo; inhibitor/antagonist; knock-down; neuroadaptation; patch clamp; protein expression; receptor; research study; restoration; transmission process; uptake

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.

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。