NEUROCHEMICAL INVOLVEMENT OF METHAMPHETAMINE SEEKING IN MICE

近年来，甲基苯丙胺（MA）的使用急剧增加，促使人们进行了认真的研究， 确定MA成瘾发展的神经生物学基础。尽管作出了重大的 进展，了解神经化学系统介导的药物寻求的动机方面 仍然不完整。一个关键的例子是我们缺乏关于乙酰胆碱（ACh）作用的信息。 MA成瘾中的受体。很大一部分MA成瘾者也自我管理胆碱能激动剂 但我们对烟碱受体可能发挥的作用只有初步的了解 对维持MA成瘾的影响为了扩展这种理解，我们需要知道MA搜索是如何 影响ACh的释放，相反，胆碱能系统的操作如何影响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延髓核中的ACh， 背外侧纹状体，海马和前额皮质的B6D2F1小鼠，训练按下杠杆， 通过长期植入的ICV插管自我给予MA。这些老鼠的结果将是 与匹配的对照组相比，后者将以轭式方式接受等量的MA（或溶媒）。这 该项目将提供与药物寻求相关的结构的神经化学数据，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共标记鉴定，以及主动和被动MA后的终末场 在B6D2F1小鼠和在科学组件6中选择性繁殖的小鼠中施用MA的差异 饮酒和MA诱导的运动敏化。除了分子信号的区域变化 事件，如ITF水平，我们将测量主动和被动MA对胆碱摄取的影响， 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。 微量注射烟碱和毒蕈碱类药物对MA寻求行为的恢复 一种紧张的刺激这些研究将解决“压力源反应”的问题，研究结果将是 与该中心的临床和行为遗传组成部分所做的工作直接相关。

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.