NEUROCHEMICAL INVOLVEMENT OF METHAMPHETAMINE SEEKING IN MICE

近年来，甲基苯丙胺(MA)的使用量急剧上升，促使一项认真的研究努力 找出MA成瘾形成的神经生物学基础。尽管有大量的 进展，对调节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关于乙酰胆碱(ACh)作用的信息。 MA成瘾中的受体。很大比例的MA成瘾者也自我给予胆碱能激动剂 吸烟产生尼古丁，但我们对尼古丁受体可能扮演的角色只有一个初步了解 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并购 影响ACh的释放，反过来，胆碱能系统的操纵如何影响MA的寻求 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ACh， B6D2F1小鼠的背外侧纹状体、海马体和前额叶皮质 通过长期植入ICV插管自我给药MA。来自这些小鼠的结果将是 与将接受等量MA(或车辆)的匹配对照组相比，他们将以轭方式接受相同数量的MA(或车辆)。这 该项目将提供与药物寻找相关的结构的神经化学数据，用于 这个研究中心。第二个目标将是研究转录因子(ITF)在体内的诱导 胆碱能细胞，胆碱能细胞和主动和被动MA后的终末野 在B6D2F1小鼠和在科学成分6中选择性培育的小鼠中应用MA的差异 饮酒和MA诱导的运动敏感化。除了分子信号的区域性变化 事件，如ITF水平，我们将测量主动和被动MA对胆碱摄取和 泡状ACh转运体。最后，第三组实验将研究特定大脑部位的影响 微量注射烟碱和毒扁豆碱对大鼠寻求MA行为的恢复作用 压力很大的刺激。这些研究将解决“压力源响应性”的问题，其结果将是 与该中心的临床和行为遗传学部分正在进行的工作直接相关。

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.