Tonic and Phasic Glutamate Release from Psychomotor Stimulants

描述（由申请人提供）：这项CEBRA R21申请涉及进一步开发、表征和使用一种先进技术，利用基于酶的微电极阵列（MEAs）研究大鼠自我给药期间特定大脑区域中l -谷氨酸的每秒变化。这项资助结合了最近开发的谷氨酸测量记录技术（Gerhardt实验室）和药物自我给药（Bardo实验室）的已知专业知识的优势。这笔拨款将适应并进一步发展成瘾研究的创新技术，这是CEBRA项目的主要目标。这项新技术有可能被许多研究者用来更好地理解神经元谷氨酸和可能的非神经元谷氨酸在成瘾中的作用。目前的提案将发展和表征一项最近开发的记录技术，在清醒和行为的大鼠中确定可卡因自我给药是否与伏隔核核心和边缘下前额皮质谷氨酸的强直性和/或阶段性释放有关。所提出的实验的机制框架取决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与药物滥用有关，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与兴奋剂暴露的长期后果有关（Kalivas, 2009）。我们的首要假设是，精神运动兴奋剂导致神经谷氨酸释放增强，以响应随后的药物管理。从健康和技术的角度来看，这一建议都是创新的。虽然谷氨酸体内平衡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，它不具备评估表征神经元释放的谷氨酸的强直和短暂相脉冲所需的时间和空间分辨率。我们的初步结果表明，在清醒的动物中，MEA方法可以测量谷氨酸的强直期和快速期水平，并且这些事件可能提供正常大脑和成瘾大脑中谷氨酸回路调节的不同且非常重要的信息。

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.