EFFECTS OF NICOTINE ON PROCESSES MEDIATED BY THE RETICULAR ACTIVATING SYSTEM

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。在一系列动物实验中，我们发现了尼古丁的潜在新作用位点。我们已经证明，全身注射尼古丁会导致睡眠状态依赖性、顶点记录、由网状激活系统（RAS）产生的 P13 中潜伏期听觉诱发电位的幅度呈剂量依赖性下降，将烟碱受体拮抗剂局部注射到 RAS 的胆碱能臂（桥脚核 [PPN]）可阻断全身尼古丁对 P13 电位（衡量唤醒），并且将烟碱受体激动剂局部注射到 PPN 中也会导致 P13 电位幅度的降低，这种效应被 PPN 注射烟碱受体拮抗剂所阻断。尼古丁还降低了海马 N40 电位，尽管这些作用不受 PPN 注射拮抗剂或激动剂的影响。在香烟烟雾中施用尼古丁来提醒自由活动的动物，对 P13 中潜伏期听觉诱发电位 (MAEP) 也有类似的影响。这些结果为解释尼古丁的抗焦虑作用提供了潜在机制，并且对于理解尼古丁在正常和病理条件下的作用具有重要意义。目标 1-3 将检验 NIC 对体内 PPN 神经元有直接作用的假设，这解释了 NIC 对唤醒的一些影响。目标 1 将描述 NIC 对重复感官输入反应的唤醒和习惯化的影响。在目标 2 中，我们将确定接触香烟烟雾对重复感官输入的唤醒和习惯的影响。目标 3 将描述母亲在怀孕期间接触香烟烟雾对 PPN 介导的体内反应的影响。目标 4 和 5 旨在检验以下假设：PPN 输出会被雌性性激素改变，并且这些改变会影响雌性动物对 NIC 的反应。目标 4 将描述雌性性激素在调节雌性大鼠 PPN 介导的反应中的作用。目标 5 将确定雌激素在调节 PPN 介导的女性对 NIC 的反应中的作用。这也提供了一个独特的机会来检查子宫内尼古丁暴露对 RAS 介导的与唤醒和注意力相关的活动的后续发展的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In a series of animal experiments, we have identified a potential novel site of action for nicotine. We have shown that systemic injection of nicotine led to a dose-dependent decrease in the amplitude of the sleep state-dependent, vertex recorded, P13 midlatency auditory evoked potential generated by the reticular activating system (RAS), that localized injections of a nicotinic receptor antagonist into the cholinergic arm of the RAS (the pedunculopontine nucleus [PPN]) blocked the effects of systemic nicotine on the P13 potential (a measure of level of arousal), and that localized injection of a nicotinic receptor agonist into the PPN also led to a decrease in the amplitude of the P13 potential, an effect blocked by PPN injection of a nicotinic receptor antagonist. Nicotine also decreased the hippocampal N40 potential although these effects were not affected by antagonist or agonist injections into the PPN. Nicotine administered in cigarette smoke to alert, free moving animals had similar effects on the P13 midlatency auditory evoked potential (MAEP). These results provide a potential mechanism for explaining the anxiolytic effects of nicotine and have important implications for understanding the effects of nicotine under normal and pathological conditions. Aims 1-3 will test the hypothesis that NIC has a direct action on PPN neurons in vivo that account for some of the effects of NIC on arousal. Aim 1 will characterize the effects of NIC on arousal and habituation of responses to repetitive sensory input. In Aim 2, we will determine the effects of exposure to cigarette smoke on arousal and habituation to repetitive sensory input. Aim 3 will characterize the effects of maternal exposure to cigarette smoke during pregnancy on PPN-mediated responses in vivo. Aims 4 and 5 are designed to test the hypothesis that PPN output is modified by female sex hormones and that these modifications affect female animals' responses to NIC. Aim 4 will characterize the role of female sex hormones in modulating PPN-mediated responses of female rats. Aim 5 will determine estrogen's role in modulating PPN-mediated responses of female rates to NIC. This also provides a unique opportunity to examine the effects of in utero nicotine exposure on the subsequent development of RAS-mediated activities related to arousal and attention.