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(申请人提供)：这项CEBRA R21申请涉及进一步开发、表征和使用一项先进技术，利用基于酶的微电极阵列(MEA)研究大鼠在自身注射可卡因过程中特定脑区L-谷氨酸的每秒变化。这笔赠款结合了最近开发的谷氨酸测量记录技术(Gerhardt实验室)和已知的药物自我给药专业知识(Bardo实验室)的优势。这笔赠款将根据CEBRA计划的主要目标，调整和进一步开发成瘾研究的创新技术。这项新技术可能会被许多研究人员用来更好地理解神经元谷氨酸(可能是非神经元谷氨酸)在成瘾中的作用(S)。目前的建议将开发和表征最近开发的清醒和行为大鼠的记录技术，以确定可卡因自我给药是否与伏隔核核心和下缘前额叶皮质谷氨酸的强直和/或相释放有关。拟议中的实验的机制框架依赖于与奖励相关的关键大脑区域谷氨酸水平的动态平衡调节信息。虽然药物滥用涉及多种神经递质系统，尤其是多巴胺，但最近的证据表明，伏隔核和相关皮质-边缘结构中的谷氨酸能张力参与了兴奋剂暴露的长期后果(Kalivas，2009)。我们的主要假设是，精神运动兴奋剂导致神经元谷氨酸释放增加，作为对随后给药的反应。从健康和技术的角度来看，这项提议都是创新的。虽然谷氨酸稳态的变化被认为是可卡因自我给药和恢复的基础(Kalivas，2009)，但细胞外谷氨酸的测量主要是通过微透析来研究的，微透析没有所需的时间和空间分辨率来评估以神经元释放为特征的紧张性和短时相谷氨酸脉冲。我们的初步结果表明，清醒动物的MEA方法可以测量谷氨酸的紧张性和快速期水平，这些事件可能提供关于正常大脑和成瘾过程中谷氨酸回路调节的不同和非常重要的信息。 公共卫生相关性：这些研究将采用一种新技术，在药物滥用的动物模型中研究快速紧张性和相性神经递质信号(谷氨酸)。研究将解决大脑中与药物滥用密切相关的区域中的慢速和快速谷氨酸信号，以及可卡因等精神运动兴奋剂的影响。这项新技术一旦开发出来，可能会被许多研究人员用来更好地了解反复使用滥用药物后大脑发生的变化。