NEUROCHEMICAL INVOLVEMENT OF METHAMPHETAMINE SEEKING IN MICE

小鼠寻找甲基苯丙胺的神经化学参与

• 批准号: 7052329
• 负责人: GREGORY P MARK
• 金额: $ 19.58万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7052329
• 关键词: acetylcholine; amygdala; antihypertensive agents; behavior; brain; choline; cholinergic receptors; clinical research; emotions; hippocampus; methamphetamine; model; motivation; neurons; nicotinic receptors; nucleus accumbens; prefrontal lobe /cortex; role; stress; transcription factor

In recent years a dramatic rise in use of methamphetamine (MA) has prompted a serious research effort to identify the neurobiological substrates that underlie the development of MA addiction. Despite substantial progress, an understanding of the neurochemical systems that mediate the motivational aspects of drugseeking remains incomplete. A key example is our lack of information on the role of acetylcholine (ACh) receptors in MA addiction. A large proportion of MA addicts also self-administer the cholinergic agonist nicotine by smoking but we have only a rudimentary understanding of the role nicotinic receptors might play on the maintenance of MA addiction. To expand this understanding, we need to know how MA-seeking affects the release of ACh and conversely, how manipulations of the cholinergic system affect MA-seeking behaviors. To accomplish the first goal we will use microdialysis to measure ACh in the nucleus accumbens, dorsolateral striatum, hippocampus and prefrontal cortex of B6D2F1 mice that are trained to press a lever to self-administer MA through chronically implanted ICV cannulae. The results from these mice will be compared to matched controls that will receive equal amounts of MA (or vehicle) in a yoked fashion. This project will provide neurochemical data on structures relevant to drug-seeking for use in other components of this research center. The second aim will be to study the induction of transcription factors (ITF's) in cholinergic cells, identified by co-labeling for ChAT, and terminal fields after active and passive MA administration inB6D2Fl mice and in mice selectively bred in Scientific Component 6 for differences in MA drinking and MA-induced locomotor sensitization. In addition to regional changes in molecular signaling events such as ITF levels, we will measure the effect of active and passive MA on the choline uptake and vesicular ACh transporters. Finally, a third set of experiments will study the impact of brain-site specific microinjections of nicotinic and muscarinic drugs on the reinstatement of MA-seeking behavior in response to a stressful stimulus. These studies will address the issue of "stressor responsivity" and the findings will be directly relevant to work being done in the clinical and the behavioral genetic components of the center.

近年来，甲基苯丙胺 (MA) 的使用急剧增加，促使人们认真研究 确定 MA 成瘾发展的神经生物学底物。尽管实质性 进步，对介导药物寻求动机方面的神经化学系统的理解 仍然不完整。一个重要的例子是我们缺乏有关乙酰胆碱 (ACh) 作用的信息 MA成瘾的受体。很大一部分 MA 成瘾者也会自行服用胆碱能激动剂 吸烟会产生尼古丁，但我们对烟碱受体可能发挥的作用只有初步的了解 关于MA成瘾的维持。为了扩大这种理解，我们需要知道如何寻求硕士学位 影响 ACh 的释放，反过来，胆碱能系统的操纵如何影响 MA 寻求 行为。为了实现第一个目标，我们将使用微透析来测量伏隔核中的乙酰胆碱， B6D2F1 小鼠的背外侧纹状体、海马体和前额叶皮层，经过训练可以按下杠杆 通过长期植入的 ICV 插管自我管理 MA。这些小鼠的结果将是 与以轭方式接收等量 MA（或车辆）的匹配控制相比。这 项目将提供与药物寻求相关的结构的神经化学数据，以用于其他组成部分 这个研究中心。第二个目标是研究转录因子（ITF）的诱导 胆碱能细胞，通过 ChAT 联合标记来识别，以及主动和被动 MA 后的末端区域 在 B6D2Fl 小鼠和科学组件 6 中选择性繁殖的小鼠中施用，以观察 MA 的差异 饮酒和 MA 引起的运动敏化。除了分子信号传导的区域变化 事件，如 ITF 水平，我们将测量主动和被动 MA 对胆碱吸收的影响， 囊泡乙酰胆碱转运蛋白。最后，第三组实验将研究大脑特定部位的影响 烟碱和毒蕈碱药物的显微注射对恢复 MA 寻求行为的影响 压力刺激。这些研究将解决“压力源反应性”问题，研究结果将 与该中心的临床和行为遗传部分所做的工作直接相关。