PRESYNAPTIC ASPECTS OF NICOTINE ADDICTION

理解尼古丁对中枢神经系统的影响的一个主要障碍是 缺乏关于神经元烟碱型乙酰胆碱作用的信息 中枢神经系统突触传递中的受体(NAChRs)尽管nAChRs是 发现于100多年前，与兰利的画笔应用 尼古丁对神经组织的作用，中枢神经系统nAChR功能的基本方面 刚刚从分子生物学和生物物理学中脱颖而出 分析。 这项建议研究了功能作用和分子组成。 中枢神经系统的突触前烟碱型乙酰胆碱受体。建议数 实验的动机是假设行为和 尼古丁的成瘾效应可能涉及激活突触前 控制中枢神经系统突触释放递质的烟碱型AChRs。这个 作为这项提议的基础的初步研究表明， 尼古丁深刻地改变了特定神经上谷氨酸的释放- 神经突触在体外和半完整的标本中(CNS切片)。 具体地说，我们建议研究尼古丁的突触前动作 关于谷氨酸能传递的实验： (1)表征突触易化和突触抑制 通过已识别的中枢神经系统突触上的nAChRs (2)测定突触前nAChRs的分布 作为这些现象背后的nAChR通道亚型(S)，使用 生物物理和分子生物学技术以及 (3)检查慢性和非传染性疾病引起的传播变化 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 在特定大脑区域的位置。此IRPG检查Low的影响 尼古丁暴露水平对突触前nAChRs激活的影响 规范释放(这项建议)及其对改变 NAChRs激活和失活状态的关系 (IRPG合作提案；J.Dani博士)。详细研究了这两个问题 慢性、低水平尼古丁暴露的这些方面可能是 剖析尼古丁成瘾的分子机制的基础。 最后，鉴于谷氨酸能传递在中国的重要性 被尼古丁改变的认知和情感行为 学习。NAChR介导的谷氨酸能传递的调节 是这一提议的基础，可能会阐明 尼古丁的短期行为影响。

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.