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: 8708806
• 负责人: Kathryn Joanna Reissner
• 金额: $ 24.9万
• 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/8708806
• 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.

神经胶质谷氨酸转运和传递在药物滥用中的作用