Tonic and Phasic Glutamate Release from Psychomotor Stimulants

描述（由申请人提供）：CEBRA R21申请涉及一种先进技术的进一步开发、表征和使用，该技术使用基于酶的微电极阵列（MEA）研究可卡因自我给药期间大鼠特定脑区中L-谷氨酸的逐秒变化。这项资助结合了最近开发的谷氨酸盐测量记录技术（格哈特实验室）与药物自我管理（巴尔多实验室）的已知专业知识的优势。这笔赠款将根据CEBRA计划的主要目标，调整并进一步开发成瘾研究的创新技术。这项新技术可能被许多研究人员用来更好地了解神经元和可能的非神经元谷氨酸在成瘾中的作用。目前的建议将开发和表征最近开发的记录技术在清醒和行为的大鼠，以确定可卡因自我管理有关的紧张和/或阶段性释放谷氨酸在核的核心和边缘前额叶皮层。所提出的实验的机制框架依赖于关键奖励相关脑区谷氨酸水平的稳态调节信息。虽然多种神经递质系统（特别是多巴胺）与药物滥用有关，但最近的证据表明，丘脑核和相关皮质边缘结构中的多巴胺能紧张与兴奋剂暴露的长期后果有关（Kalivas，2009年）。我们的总体假设是，精神兴奋剂导致增强神经元谷氨酸释放响应于随后的药物管理。该提案从健康和技术角度都具有创新性。虽然已提出谷氨酸稳态的变化是可卡因自我给药和恢复的基础（Kalivas，2009），但主要通过微透析研究了细胞外谷氨酸测量，微透析不具有评价表征神经元释放的谷氨酸的紧张性和短暂阶段性脉冲所需的时间和空间分辨率。我们的初步研究结果表明，MEA方法在清醒的动物可以测量紧张和快速阶段性水平的谷氨酸和事件可能会提供不同的和非常重要的信息，在正常的大脑和成瘾的谷氨酸回路的调节。

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.