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， 它是导致过早死亡的主要原因。 虽然多个 精神药理学作用有助于烟草滥用，尼古丁是 被认为是强化习惯的主要成分。 尼古丁与烟碱乙酰胆碱受体（nAChR）结合。 的 尼古丁释放速率和暴露时间决定了 nAChR的群体分布在封闭的功能状态中， 离子传导的、脱敏的或长期灭活的。 吸烟者摄入 每支烟都有尼古丁的小脉冲 这些尼古丁的峰值 维持低水平的尼古丁，随着重复 白天抽烟。 该研究将检验以下假设： 尼古丁的脉冲可以激活nAChRs，引起多巴胺的释放， 产生主要通过中脑边缘多巴胺能介导的“奖励”效应 系统 然而，持续低水平的尼古丁可能会导致 nAChR的显著脱敏或长期失活， 耐受性或非奖赏介导的戒断症状的基础 途径。 膜片钳电生理学，钙测量， 将使用免疫细胞化学来研究该假设。 腹侧被盖区（VTA）神经元突触到低 将检查髓核神经元的密度培养物以确定 尼古丁如何引起多巴胺释放 VTA脑切片和组织培养 的腹侧被盖区和缰核神经元将被用来了解时间尺度， nAChR脱敏和长期失活的影响，以及 从这些国家恢复过来。 烟碱AChR激活，导致DA 由中脑边缘神经元释放，可以提供强化奖励， 引发烟草滥用。 吸烟者可能会进一步吸烟， 在更长的时间内用尼古丁来控制 nAChR脱敏和失活的程度可能是 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.