Neurobiology of nicotine reward and dependence in mice

描述(申请人提供)：尼古丁被认为是导致人类习惯性吸烟的烟草烟雾中的主要精神活性成分之一。尼古丁能产生令人愉悦的欣快感，也能增强其他奖赏刺激(即奖赏促进)的效果。此外，长期服用尼古丁引起的适应会导致尼古丁戒断期间大脑奖赏功能和躯体体征的缺陷。这三种与尼古丁消费相关的效应(即急性尼古丁的愉悦效应、尼古丁诱导的其他奖励的促进作用以及令人厌恶的尼古丁戒断综合症)都被假设为提供重要的动机来源，使致命的吸烟习惯永久化。拟议项目的目标有三个。具体目标1将试图确定在尼古丁的主要强化作用中关键参与的特定烟碱型乙酰胆碱受体(NAChR)亚单位。具体目标2将试图确定nAchR亚基在急性尼古丁的奖赏增强效应中起关键作用。最后，特殊目标3将尝试确定特定的nAChR亚基，这些亚基与大脑奖赏功能缺陷和与尼古丁戒断相关的躯体迹象密切相关。拟议的研究将在野生型小鼠和转基因小鼠中进行，在这些小鼠中，A7或？4 nAChR亚基发生零突变，或其中4个nAChR亚基对尼古丁过敏(分别为A7-/-、？4-/-和Leu9‘Ala小鼠)。之所以选择这些亚基，是因为它们的定位意味着它们与拟议研究中调查的尼古丁的影响有关。为了确定对尼古丁依赖的各个方面至关重要的nAChR亚基，将使用静脉注射尼古丁自我给药和颅内自我刺激(ICSS)程序。尼古丁自身给药和尼古丁诱导的ICSS阈值降低将分别作为尼古丁和尼古丁诱导的奖赏易化效应的增强效应的指标。自发戒烟期间ICSS阈值的升高(即奖赏缺失)和戒断的躯体迹象增加将分别作为尼古丁戒断的情感和躯体成分的衡量标准。这些研究将确定含有A7、A4和/或A4亚基的nAChRs是否关键地参与了尼古丁的调节作用，而尼古丁被认为是维持吸烟习惯的关键激励因素。将产生完整的尼古丁剂量反应函数。未来的工作将使用更多的突变小鼠来研究其他nAchR亚单位在相同现象中的潜在作用。相关性：更好地理解尼古丁的奖赏效应、尼古丁的奖赏增强效应和尼古丁戒烟的厌恶效应背后的神经生物学底物，将提供对导致人类持续使用烟草的动机来源的洞察，并可能导致新的和改进的行为和药物治疗，以帮助吸烟者戒烟。

DESCRIPTION (provided by applicant): It is thought that nicotine is one of the main psychoactive ingredients in tobacco smoke that leads to habitual tobacco smoking in humans. Nicotine induces pleasurable euphoric-like effects and also enhances the effects of other rewarding stimuli (i.e., reward facilitation). Further, adaptations induced by chronic nicotine administration result in deficits in brain reward function and somatic signs during nicotine withdrawal. These three effects associated with nicotine consumption (i.e., pleasurable effects of acute nicotine, nicotine- induced facilitation of other rewards, and the aversive nicotine withdrawal syndrome) are all hypothesized to provide important sources of motivation that perpetuate the deadly tobacco smoking habit. The goals of the proposed project are threefold. Specific Aim 1 will attempt to identify specific nicotinic acetylcholine receptor (nAChR) subunits critically involved in the primary reinforcing effects of nicotine. Specific Aim 2 will attempt to identify nAchR subunits critically involved in the reward enhancing effects of acute nicotine. Finally, Specific Aim 3 will attempt to identify specific nAChR subunits which are critically involved in the brain reward function deficits and somatic signs associated with nicotine withdrawal. The proposed studies will be carried out in wildtype mice and genetically modified mice in which a7 or ¿4 nAChR subunits have been null mutated or in which a 4 nAChR subunits have been rendered hypersensitive to nicotine (a7-/-, ¿4-/-, and Leu9'Ala mice, respectively). These subunits have been selected because their localization implicates them in the effects of nicotine investigated in the proposed studies. To identify nAChR subunits critical to the various aspects of nicotine dependence, intravenous nicotine self-administration and intracranial self-stimulation (ICSS) procedures will be utilized. Nicotine self-administration and nicotine- induced lowering of ICSS thresholds will serve as measures of the reinforcing effects of nicotine and nicotine-induced facilitation of reward, respectively. Elevations of ICSS thresholds (i.e., reward deficits) and increased somatic signs of withdrawal during spontaneous nicotine withdrawal will serve as measures of the affective and somatic components of nicotine withdrawal, respectively. These studies will determine whether nAchRs containing the a7, ¿4 and/or a4 subunits are critically involved in mediating effects of nicotine that are hypothesized to be crucial motivating factors in maintaining the tobacco smoking habit. Full nicotine dose-response functions will be generated. Future work will use additional mutant mice to investigate the potential role of other nAchR subunits in the same phenomena. Relevance: Improved understanding of the neurobiological substrates that underlie the rewarding effects of nicotine, the reward-enhancing effects of nicotine and the aversive effects of nicotine abstinence will provide insights into the sources of motivation that result in persistent use of tobacco in humans, and is likely to lead to new and improved behavioral and pharmacological treatments to assist smokers in quitting.