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

基本信息

批准号：
9059846
负责人：
Kathryn Joanna Reissner
金额：
$ 1.37万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/9059846
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

项目摘要

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.

神经胶质谷氨酸转运和传播对药物滥用的贡献成瘾最隐蔽的临床特征之一是长期服药后很容易复发。节制。现有证据表明，细胞核内谷氨酸稳态的破坏伏隔核是导致这种慢性复发脆弱性的一个机制。谷氨酸稳态是指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。长期接触可卡因后发生的长期神经适应包括胱氨酸-谷氨酸交换器（xCT）催化亚基的功能和蛋白质表达下降和高亲和力神经胶质谷氨酸转运蛋白 GLT-1，非突触细胞外的两个整体调节因子谷氨酸。因此，在服用可卡因后测量到细胞外谷氨酸浓度降低伏隔核的自我给药。使用 N-乙酰半胱氨酸 (NAC) 或头孢曲松会损害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久破坏的调节机制体内平衡及其对成瘾的贡献，我采用了反义击倒策略确定 GLT-1 和 xCT 在大鼠成瘾恢复模型中的相对贡献。初步的数据表明，神经胶质GLT-1的表达，而不是xCT，是治疗效果的关键介质。 NAC。因此，该提案的一个目标是检验以下假设：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，进而影响谷氨酸的稳态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奖励阶段使用（i）体内微透析来测量遗传后的谷氨酸浓度操纵 GLT-1，以及 (ii) 膜片钳电生理学来比较培养基的生理特性多刺神经元（mEPSC、AMPA：NMDA 比率、[神经胶质源性缓慢内向电流]）在这些相同的条件下状况。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）代谢型谷氨酸受体在这些过程中的参与。