Tonic and Phasic Glutamate Release from Psychomotor Stimulants

精神运动兴奋剂的强效和阶段性谷氨酸释放

• 批准号: 8322257
• 负责人: Greg A. Gerhardt
• 金额: $ 18.56万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8322257
• 关键词: Address; Animal Model; Animals; Area; Behavior; Brain; Brain region; Cocaine; Data; Development; Devices; Dopamine; Drug abuse; Enzymes; Event; Glutamates; Goals; Grant; Head; Health; Homeostasis; Impulsivity; Intravenous; Lead; Measurement; Measures; Methods; Microdialysis; Microelectrodes; Modification; Morphologic artifacts; Neurons; Neurotransmitters; Noise; Nucleus Accumbens; Pattern; Pharmaceutical Preparations; Physiologic pulse; Prefrontal Cortex; Rattus; Regulation; Research; Research Personnel; Resolution; Rest; Rewards; Role; Saline; Sampling; Self Administration; Self-Administered; Signal Transduction; Source; Staging; Stress; Structure; System; Tail; Techniques; Technology; Time; Training; Work; addiction; awake; base; drug of abuse; extracellular; improved; innovation; new technology; programs; prototype; research study; response; stimulant abuse

DESCRIPTION (provided by applicant): This CEBRA R21 application involves the further development, characterization and use of an advanced technology to study second-by-second changes in L-glutamate in specific brain regions in rats using enzyme- based microelectrode arrays (MEAs) during self-administration of cocaine. This grant combines the strengths of a recently developed recording technology for glutamate measures (Gerhardt lab) with known expertise in drug self-administration (Bardo lab). This grant will adapt and further develop an innovative technique for addiction research, as per the primary goals of the CEBRA program. The new technology can be potentially used by numerous investigators to better understand the role(s) of neuronal and possibly non- neuronal glutamate in addiction. The current proposal will develop and characterize a recently developed recording technology in awake and behaving rats to determine if cocaine self-administration is related to tonic and/or phasic release of glutamate in the nucleus accumbens core and infralimbic prefrontal cortex. The mechanistic framework for the proposed experiments rests on information about the homeostatic regulation of glutamate levels in critical reward-relevant brain regions. While a variety of neurotransmitter systems are involved in drug abuse, particularly dopamine, recent evidence indicates that glutamatergic tone in nucleus accumbens and related cortico-limbic structures is involved in the long-lasting consequences of stimulant exposure (Kalivas, 2009). Our overarching hypothesis is that psychomotor stimulants lead to enhanced neuronal glutamate release in response to subsequent administration of drugs. The proposal is innovative from both health and technological perspectives. While the changes in glutamate homeostasis have been proposed to underlie cocaine self-administration and reinstatement (Kalivas, 2009), extracellular glutamate measurements have been studied primarily by microdialysis, which does not have the temporal and spatial resolution required to evaluate both tonic and brief phasic pulses of glutamate that characterize neuronal release. Our preliminary results show that the MEA methods in awake animals can measure both tonic and rapid phasic levels of glutamate and that the events may provide different and very important information regarding regulation of glutamate circuitry in the normal brain and in addiction. PUBLIC HEALTH RELEVANCE: These studies will adapt a new technology for investigating rapid tonic and phasic neurotransmitter signaling (glutamate) in an animal model of drug abuse. Studies will address slow and fast glutamate signals in brain areas critically involved with drug abuse and the effects of psychomotor stimulant drugs, such as cocaine. This new technology, once developed, can possibly be used by many investigators to better understand changes to the brain that occur following repeated use of drugs of abuse.

描述（由申请人提供）：此CEBRA R21申请涉及先进技术在大鼠中使用基于酶的微电极阵列（MAS）在大鼠中的特定大脑区域的L-谷氨酸次秒变化的进一步发展，表征和使用。该赠款结合了最近开发的用于谷氨酸措施的记录技术（Gerhardt Lab）的优势以及药物自我管理方面的已知专业知识（Bardo Lab）。根据CEBRA计划的主要目标，该赠款将适应成瘾研究的创新技术。这项新技术可以被众多研究人员使用，以更好地了解成瘾中神经元和可能非神经谷氨酸的作用。当前的提案将在清醒和行为大鼠中发展并表征最近开发的记录技术，以确定可卡因自我给药是否与乙酸谷氨酸核中的补体和/或相位释放有关。拟议实验的机械框架取决于有关与临界奖励相关的大脑区域中谷氨酸水平的稳态调节的信息。虽然各种神经递质系统涉及药物滥用，尤其是多巴胺，但最近的证据表明，伏伏核和相关的皮质膜结构中的谷氨酸能张力与刺激性暴露的长期后果有关（Kalivas，2009）。我们的总体假设是，精神运动刺激剂会导致神经元的谷氨酸释放增强，以响应随后的药物给药。从健康和技术角度来看，该提案都是创新的。 While the changes in glutamate homeostasis have been proposed to underlie cocaine self-administration and reinstatement (Kalivas, 2009), extracellular glutamate measurements have been studied primarily by microdialysis, which does not have the temporal and spatial resolution required to evaluate both tonic and brief phasic pulses of glutamate that characterize neuronal release.我们的初步结果表明，清醒动物中的MEA方法可以测量谷氨酸的滋补和快速阶段水平，并且这些事件可能会提供有关正常大脑和成瘾中谷氨酸电路调节的不同且非常重要的信息。 公共卫生相关性：这些研究将适应一种新技术，用于研究药物滥用动物模型中的快速滋补和阶段性神经递质信号传导（谷氨酸）。研究将解决与药物滥用有关的大脑区域的缓慢和快速的谷氨酸信号，以及心理刺激药物（例如可卡因）的影响。这项一旦开发的新技术可能会被许多调查人员使用，以更好地理解在反复使用滥用药物后发生的大脑变化。