High-speed detection of stimulant-induced cortical ACh release

高速检测兴奋剂诱导的皮质乙酰胆碱释放

• 批准号: 7139406
• 负责人: JOHN P BRUNO
• 金额: $ 33.29万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-25 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7139406
• 关键词: amphetamines; central nervous system stimulants; choline; microelectrodes; nicotine; wakefulness

DESCRIPTION (provided by applicant): This proposal focuses on the effects of stimulant drugs on cortical cholinergic transmission. It is driven by the theory that changes in cortical cholinergic transmission mediate the hyper-attentional biases postulated to contribute to processes of craving and relapse in addiction. This monopolization of attentional resources bias the addict toward the processing of drug-related cues and reduces the likelihood of evaluating alternative behaviors and coping strategies. A more thorough understanding of the neurobiological mechanisms underlying these cognitive changes will aid in the development of more efficacious ways to treat this major public health problem. The proposed experiments utilize an innovative enzyme-selective microelectrode array to reveal the effects of psychostimulants (nicotine and amphetamine) on cortical neurochemistry. The studies are designed to validate the rapid, in situ detection of extracellular ACh using these microelectrodes as a sensitive measure of cholinergic transmission. ACh-derived signals will be determined at a temporal (i.e. second-by-second) and spatial (i.e. 10-20 mu m) resolution that far exceeds conventional techniques. We will first test this electrochemical method in anaesthetized rats (in order to optimize several electrochemical, neurobiological, and procedural variables). After optimizing the parameters of electrochemical recording, we will then validate the method in awake rats following the administration of psychostimulants and environmental stimuli - stimuli that have been shown to increase cortical ACh release following more conventional methods. But, this is only a starting point for a series of important experiments on the neurochemistry of attentional mechanisms in conditions of drug abuse. For the first time, we will be able to study cholinergic transmission within a time-frame that is consistent with the cognitive processes that have been linked to cortical cholinergic transmission and believed to underlie compulsive drug use. In much the same fashion that enhanced voltammetric techniques, and the focus on phasic DA release, have revealed new perspectives on the contributions of accumbens DA to drug-seeking behaviors the ACh- and choline-sensitive microelectrode arrays will allow us to measure cholinergic transmission in subsecond time periods and within discrete regions in order to address important issues in addiction.

描述（由申请人提供）：本提案重点关注兴奋剂药物对皮质胆碱能传递的影响。它是由皮质胆碱能传递的变化介导的过度注意偏差假设有助于成瘾的渴望和复发的过程的理论驱动的。这种对注意力资源的垄断使成瘾者倾向于处理与药物有关的线索，并降低了评估替代行为和应对策略的可能性。对这些认知变化背后的神经生物学机制的更透彻理解将有助于开发更有效的方法来治疗这一重大公共卫生问题。拟议的实验利用一种创新的酶选择性微电极阵列，以揭示精神兴奋剂（尼古丁和安非他明）对皮层神经化学的影响。这些研究的目的是验证使用这些微电极作为胆碱能传输的敏感措施的细胞外乙酰胆碱的快速，原位检测。乙酰胆碱衍生的信号将以远超过传统技术的时间（即逐秒）和空间（即10-20 μ m）分辨率来确定。我们将首先在麻醉大鼠中测试这种电化学方法（以优化几个电化学，神经生物学和程序变量）。在优化电化学记录的参数后，我们将在清醒的大鼠中验证该方法，随后给予精神兴奋剂和环境刺激-这些刺激已被证明可以增加皮质ACh的释放。但是，这只是一个起点，一系列的重要实验的神经化学的注意力机制在药物滥用的条件。这是第一次，我们将能够在一个时间框架内研究胆碱能传递，这与认知过程是一致的，这些认知过程与皮质胆碱能传递有关，并被认为是强迫性药物使用的基础。在几乎相同的方式，增强伏安技术，并专注于阶段DA释放，揭示了新的观点的贡献，多巴胺的药物寻求行为的乙酰胆碱和胆碱敏感的微电极阵列将使我们能够测量胆碱能传输在亚秒的时间段内，在离散的区域，以解决重要的问题，成瘾。