Neurobiology of nicotine reward and dependence in mice

描述（由申请人提供）：尼古丁被认为是烟草烟雾中导致人类习惯性吸烟的主要精神活性成分之一。尼古丁会引起愉悦的欣快感，也会增强其他奖励刺激的效果（即奖励促进）。此外，慢性尼古丁给药诱导的适应性导致尼古丁戒断期间大脑奖励功能和躯体体征的缺陷。与尼古丁消耗有关的这三种效应（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征）都被假设为提供了使致命的吸烟习惯持续存在的重要动机来源。拟议项目的目标有三个方面。特异性目的1将试图确定特定的尼古丁乙酰胆碱受体（nAChR）亚基，这些亚基在尼古丁的主要强化作用中起关键作用。特异性目标2将试图确定nAchR亚单位关键参与急性尼古丁的奖励增强效应。最后，Specific Aim 3将尝试确定特定的nAChR亚基，这些亚基在尼古丁戒断相关的大脑奖励功能缺陷和躯体体征中起关键作用。拟议的研究将在a7或¿4 nAChR亚基发生零突变或4 nAChR亚基对尼古丁过敏的野生型小鼠和转基因小鼠（分别为a7-/-，¿4-/-和Leu9'Ala小鼠）中进行。之所以选择这些亚基，是因为它们的定位与拟议研究中所调查的尼古丁效应有关。为了确定对尼古丁依赖的各个方面至关重要的nAChR亚基，将使用静脉尼古丁自我给药和颅内自我刺激（ICSS）程序。尼古丁的自我给药和尼古丁诱导的ICSS阈值的降低将分别作为尼古丁和尼古丁诱导的奖励促进作用的增强措施。在自发尼古丁戒断期间，ICSS阈值的升高（即奖励缺陷）和戒断的躯体体征的增加将分别作为尼古丁戒断的情感和躯体成分的测量。这些研究将确定含有a7，¿4和/或a4亚基的nachr是否在尼古丁的介导作用中起关键作用，而尼古丁被假设为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亚基在相同现象中的潜在作用。相关性：对尼古丁的奖励效应、尼古丁的奖励增强效应和尼古丁戒断的厌恶效应背后的神经生物学基础的进一步了解，将有助于深入了解导致人类持续使用烟草的动机来源，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.