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: 8848449
• 负责人: Kathryn Joanna Reissner
• 金额: $ 0.81万
• 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/8848449
• 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; Relative (related person); 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; 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.

神经胶质谷氨酸运输和传播对药物滥用的贡献 成瘾的最阴险的临床特征之一是延长后复发的脆弱性 节制。现有证据表明，核内谷氨酸稳态的破坏 a伏型是造成这种慢性复发脆弱性的促进机制。谷氨酸稳态指的是 调节突触的突触外和突触神经元谷氨酸浓度之间的平衡 可塑性。在长期暴露于可卡因后发生的持久神经适应症中 胱氨酸 - 谷氨酸交换器（XCT）的催化亚基的功能和蛋白质表达降低 和高亲和力神经胶质谷氨酸转运蛋白GLT-1，两个非突触外细胞外的积分调节剂 谷氨酸。因此，可卡因后测量细胞外谷氨酸浓度降低 伏隔核中的自我给药。 N-乙酰半胱氨酸（NAC）或 头孢曲松会损害可卡因的恢复原状，并增加GLT-1和XCT的表达。 [作为一种手段 更充分地理解负责忍受谷氨酸中断的同性同层机制 稳态及其对成瘾的贡献，我采用了反义敲低策略 确定在成瘾的大鼠恢复模型中GLT-1和XCT的相对贡献。初步的 数据表明，Glial GLT-1的表达（而不是XCT的表达）是治疗作用的关键介体 NAC。因此，该提案的目标是检验可卡因暴露后神经胶质适应的假设 影响谷氨酸的释放和摄取，进而影响谷氨酸和谷氨酸的体内平衡 可卡因诱导的细胞和突触神经适应。]这将在指导期间完成 使用（i）在体内微透析的奖励阶段，以测量遗传后的谷氨酸浓度 操纵GLT-1和（ii）斑块夹电生理学以比较培养基的生理特性 在这些相同的情况下 状况。奖励独立阶段提出的实验将继续进行这些研究 并研究（iii）代谢型谷氨酸受体在这些过程中的参与。