The alpha5 Nicotinic Acetylcholine Receptor Subunit in Nicotine Dependence

说明(申请人提供)：烟草成瘾对个人和社会的健康和经济状况有严重的负面影响。尼古丁被认为是导致人类吸烟者烟瘾的主要强化成分[2]。尼古丁在大脑中的主要作用部位是烟碱型乙酰胆碱受体(NAChR)，它由不同亚单位的离散组合组成。A5亚单位最近引起了人们的注意，因为遗传连锁研究表明，a5 nAChR亚单位基因(CHRNA5)的多态增加了人类吸烟者对尼古丁依赖的易感性[11，12]。此外，将该亚基插入到某些nAChR亚型中已被证明改变了非洲爪哇卵母细胞中受体的脱敏和激活动力学[5]。这项建议的目的是确定含有AS的nAChRs在小鼠尼古丁奖赏、依赖和戒断中的作用。静脉给药程序被认为是衡量滥用药物强化特性的最可靠的方法。在特定的目标I中，我将通过检测野生型(WT)小鼠和a5 nAChR亚单位基因零突变(a5-/-)小鼠的静脉注射尼古丁自我给药来研究a5亚单位在尼古丁奖励中的作用。颅内自我刺激程序(ICSS)被认为是对大脑自然奖赏通路功能的直接测量。因此，在特定的目标二中，我将通过测量尼古丁诱导的WT和a5-/-小鼠ICSS阈值的降低，来研究含有a5的nAChRs在调节急性给予尼古丁对大脑奖励系统的刺激效应中的作用。最后，在特定的目标III中，我将研究含有AS的nAChRs在WT和a5-/-小鼠自发尼古丁戒断过程中奖赏缺失的表达中的作用；自发尼古丁戒断期间ICSS阈值的升高将作为与尼古丁戒断相关的奖赏缺失的衡量标准。我推测，含砷的nAChRs在调节尼古丁对大脑奖赏回路的作用中起着重要作用，从而调节尼古丁的自我给药行为、尼古丁的急性奖赏增强效应以及与尼古丁戒断相关的奖赏赤字。总而言之，这些数据可能揭示尼古丁奖赏、依赖和戒断背后的神经生物学机制的基本见解。重要的是，这些发现可能会导致开发出对人类戒烟和/或预防复发有效的新疗法。

DESCRIPTION (provided by applicant): Tobacco addiction has a significant negative impact on the health and economic status of the individual and society. Nicotine is considered to be the primary reinforcing component responsible for tobacco addiction in human smokers [2]. Nicotine's main site of action in the brain is the nicotinic acetylcholine receptor (nAChR), which is composed of discrete combinations of various subunits. The a5 subunit has garnered recent attention based on genetic linkage studies suggesting polymorphisms in the a5 nAChR subunit gene (CHRNA5) increase susceptibility to nicotine dependence in human smokers [11, 12]. Further, insertion of this subunit into certain nAChR subtypes has been shown to alter receptor desensitization and activation kinetics in Xenopus oocytes [5]. The objective of this proposal is to determine the role ofaS-containing nAChRs in nicotine reward, dependence and withdrawal in mice. The intravenous self-administration procedure is considered to be the most reliable measure of the reinforcing properties of drugs of abuse. In Specific Aim I, I will examine the role of the a5 subunit in nicotine reward by examining intravenous nicotine self-administration in wildtype (WT) mice and mice with a null mutation of the a5 nAChR subunit gene (a5-/-). The intracranial self-stimulation procedure (ICSS) is considered to be a direct measure of the functioning of the brain's natural reward pathways. Thus, in Specific Aim II, I will investigate the role of a5- containing nAChRs in regulating the stimulatory effects of acutely administered nicotine on brain reward systems by measuring nicotine-induced lowering of ICSS thresholds in WT and a5-/- mice. Finally, in Specific Aim III, I will examine the role of the aS-containing nAChRs in the expression of reward deficits during spontaneous nicotine withdrawal in WT and a5-/- mice; elevation of ICSS thresholds during spontaneous nicotine withdrawal will serve as a measure of the reward deficit associated with nicotine withdrawal. I hypothesize that aS-containing nAChRs play an important role in regulating the actions of nicotine on the brain reward circuits, and thereby regulate nicotine self-administration behavior, the acute reward-enhancing effects of nicotine, and the reward deficit associated with nicotine withdrawal. Together, these data may reveal fundamental insights into the neurobiological mechanisms underlying nicotine reward, dependence and withdrawal. Importantly, these findings could lead to the development of novel therapeutics efficacious for smoking cessation and/or relapse prevention in humans.