Contributions of Glial Glutamate Transport and Transmission to Drug Abuse

神经胶质谷氨酸运输和传递在药物滥用中的作用 成瘾最隐蔽的临床特征之一是在长期吸毒后易复发。 禁欲。现有证据表明，细胞核内谷氨酸稳态的破坏 伏隔是导致这种慢性复发脆弱性的一种机制。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。在长期接触可卡因后发生的长期神经适应中，有 半胱氨酸-谷氨酸交换器(XCT)催化亚单位功能和蛋白表达降低 和高亲和力胶质谷氨酸转运体GLT-1，这是非突触细胞外的两个完整调节因子 谷氨酸。因此，可卡因后细胞外谷氨酸浓度降低。 伏隔核内的自我管理。使用N-乙酰半胱氨酸(NAC)或 头孢曲松影响对可卡因的恢复，并增加GLT-1和XCT的表达。[作为一种手段 更全面地了解导致谷氨酸持续中断的变态机制 动态平衡及其对成瘾的贡献，我采用了反义击倒策略来 确定GLT-1和XCT在大鼠戒断成瘾模型中的相对作用。初步 有数据表明，胶质细胞GLT-1的表达，而不是XCT，是急性髓细胞白血病疗效的关键调节因子。 南汽。因此，这项提议的一个目标是检验这一假设，即可卡因暴露后神经胶质细胞的适应 影响谷氨酸的释放和摄取，进而影响谷氨酸的动态平衡和 可卡因诱导的细胞和突触神经适应。]这将在指导期间完成 该奖项的阶段使用(I)体内微透析来测量遗传基因后的谷氨酸浓度 GLT-1的操作，以及(Ii)膜片钳电生理学比较介质的生理特性 刺状神经元(mEPSCs，AMPA：NMDA比率，[神经胶质细胞衍生的慢内向电流]) 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 以及研究(Iii)代谢性谷氨酸受体在这些过程中的参与。

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.