CELLULAR AND MOLECULAR ASPECTS OF NICOTINE ADDICTION

描述：(申请人摘要) 在美国，烟草使用每年导致40万人死亡，使 它是导致过早死亡的主要原因。尽管有多个 精神药理学效应导致烟草滥用，尼古丁是 被认为是强化习惯的主要因素。 尼古丁与烟碱型乙酰胆碱受体(NAChRs)结合。这个 尼古丁的释放速度和接触时间决定了 NAChRs的种群分布在封闭的功能状态中， 离子传导、失敏或长期失活。吸烟者吸入一种 每支香烟的尼古丁脉搏很小。这些尼古丁的高峰期 尼古丁水平维持在较低水平，并随着反复摄入而增加 白天抽香烟。这项研究将检验以下假设： 尼古丁的脉冲可以激活nAChRs，引起多巴胺释放和 产生“奖赏”效应主要通过中脑边缘多巴胺能 系统。然而，持续的低尼古丁水平可能会导致 NAChRs显著脱敏或长期失活，可能 非奖赏介导的耐受性或戒断症状的各个方面 小路。 膜片钳电生理学、钙测量和 将使用免疫细胞化学来研究这一假说。 腹侧被盖区(VTA)神经元突触Low的显微外植体 伏隔核神经元的密度培养将被检查以确定 尼古丁是如何引起多巴胺释放的。VTA脑片和组织培养 VTA和缰核神经元将被用来理解时间尺度和 NAChR脱敏和长期失活以及 从这些州恢复过来。尼古丁AChR激活，导致DA 由中脑边缘神经元释放，可能会提供增强的奖励， 引发烟草滥用。可能会出现进一步的吸烟动力，因为吸烟者 在更长的时间范围内用尼古丁给自己服药以控制 对nAChR脱敏和失活的程度可能是某些方面的基础 耐受性和戒断症状。

DESCRIPTION: (Applicant's Abstract) In the United States, tobacco use causes 400,000 deaths a year, making it the leading cause of premature death. Although multiple psychopharmacological effects contribute to tobacco abuse, nicotine is accepted as the primary component that reinforces the habit. Nicotine binds to nicotinic acetylcholine receptors (nAChRs). The rate of nicotine delivery and the time of exposure dictates how the populations of nAChRs distributes among functional states that are closed, ion conducting, desensitized, or long term inactivated. Smokers take in a small pulse of nicotine with each cigarette. These peaks of nicotine ride on a maintained low level of nicotine that increases with repeated cigarettes during the day. The research will test the following hypothesis: The pulse of nicotine could activate nAChRs that evoke dopamine release and produce "rewarding" effects mediated mainly via the mesolimbic dopaminergic system. The sustained low levels of nicotine, however, could cause significant desensitization or longer-term inactivation of nAChRs that may underlie tolerance or aspects of withdrawal symptoms mediated by non-reward pathways. Patch-clamp electrophysiology, calcium measurements, and immunocytochemistry will be used to investigate the hypothesis. Microexplants of ventral tegmental area (VTA) neurons synapsing onto low density cultures of nucleus accumbens neurons will be examined to determine how nicotine evokes dopamine release. VTA brain slices and tissue cultures of VTA and habenula neurons will be used to understand the time scales and effects of nAChR desensitization and long-term inactivation as well as recovery from those states. Nicotinic AChR activation, leading to DA release by mesolimbic neurons, may provide the reinforcing reward that initiates tobacco abuse. A further drive to smoke may arise because smokers are medicating themselves with nicotine on longer time scales to control the degree to nAChR desensitization and inactivation that may underlie aspects of tolerance and withdrawal symptoms.