PRESYNAPTIC ASPECTS OF NICOTINE ADDICTION

了解尼古丁对中枢神经系统影响的主要障碍是 缺乏关于神经元烟碱乙酰胆碱作用的信息 受体（nAChR）在CNS突触传递中的作用。虽然nAChR 100多年前，兰利的画笔应用 尼古丁对神经组织的影响，CNS nAChR功能的基本方面 才刚刚从分子生物学和生物物理学 分析。 本提案审查了功能作用和分子组成的 突触前烟碱乙酰胆碱受体在中枢神经系统。拟议 实验的动机是假设，行为和 尼古丁的成瘾作用可能涉及激活突触前神经元， 烟碱AChR，其控制CNS突触处的递质释放。的 初步研究表明， 尼古丁深刻地改变了特定神经中谷氨酸的释放， 体外和半完整制备物（CNS切片）中的神经突触。 具体地说，我们建议研究尼古丁的突触前作用 通过实验证明： (1)表征突触易化和抑制介导的 通过nAChR在一个确定的CNS突触 (2)确定突触前nAChRs的分布 作为这些现象背后的nAChR通道亚型，使用 生物物理和分子生物学技术， (3)检查慢性疾病以及 急性尼古丁暴露 尼古丁依赖伴随着脑脊液尼古丁水平， 亚微摩尔范围以及高亲和力尼古丁结合的变化 在特定的大脑区域。本IRPG检查了低血糖的影响， 水平尼古丁暴露对突触前nAChR激活的影响， 规范释放（本提案）及其对改变 nAChRs激活和失活状态之间的关系 （IRPG合作提案; J. Dani博士）。对两者的详细研究 慢性低水平尼古丁暴露的这些方面可能是 这是剖析尼古丁成瘾分子机制的基础。 最后，考虑到传播的重要性， 认知和情感行为被尼古丁改变， 问题研究nAChR介导的对神经递质传递的调节， 这一建议的基础可以阐明机制的基础上， 尼古丁的短期影响

A major obstacle to understanding the CNS effects of nicotine has been the lack of information on the role of neuronal nicotinic acetylcholine receptors (nAChRs) in CNS synaptic transmission. Although nAChRs were discovered more than 100 years ago, with Langley's paintbrush application of nicotine to neural tissue, fundamental aspects of CNS nAChR function have only just emerged from molecular biological and biophysical analyses. This proposal examines the functional role and molecular composition of presynaptic nicotinic acetylcholine receptors in the CNS. The proposed experiments are motivated by the hypothesis that the behavioral and addictive effects of nicotine may involve activation of presynaptic nicotinic AChRs that control transmitter release at CNS synapses. The preliminary studies that are the groundwork of this proposal, reveal that nicotine profoundly alters the release of glutamate at specific nerve- nerve synapses both in vitro and in semi-intact preparations (CNS slice). Specifically, we propose to examine the presynaptic actions of nicotine on glutamatergic transmission by experiments that: (1) characterize the synaptic facilitation and depression mediated by nAChRs at an identified CNS synapse (2) determine the distribution of presynaptic nAChRs as well as the nAChR channel subtype(s) underlying these phenomena using biophysical, and molecular biological techniques and (3) examine changes in transmission induced by chronic as well as by acute nicotine exposure. Nicotine dependence is accompanied by CSF nicotine levels in the submicromolar range as well as changes in high affinity nicotine binding sites in specific brain regions. This IRPG examines the effects of low level nicotine exposure on the activation of presynaptic nAChRs that regulate release (this proposal) and its effects on altering the relationship between activated and inactivated states of nAChRs (collaborative IRPG proposal; Dr J. Dani). Detailed study of both of these aspects of chronic, low level nicotine exposure are likely to be fundamental to dissecting the molecular mechanisms of nicotine addiction. Finally, in view of the prominence of glutamatergic transmission in cognitive and affective behaviors that are altered by nicotine, the studies. of nAChR-mediated regulation of glutamatergic transmission that are the basis of this proposal may elucidate mechanisms underlying the short term behavioral effects of nicotine.