The alpha5 Nicotinic Acetylcholine Receptor Subunit in Nicotine Dependence

描述（由申请人提供）：烟草成瘾对个人和社会的健康和经济状况有显著的负面影响。尼古丁被认为是导致人类吸烟者烟草成瘾的主要强化成分。尼古丁在大脑中的主要作用部位是尼古丁乙酰胆碱受体（nAChR），它由各种亚基的离散组合组成。最近，基于遗传连锁研究，a5 nAChR亚基基因（CHRNA5）的多态性增加了人类吸烟者对尼古丁依赖的易感性，a5亚基引起了人们的关注[11,12]。此外，该亚基插入某些nAChR亚型已被证明可以改变非洲爪蟾卵母细胞[5]中的受体脱敏和激活动力学。本研究的目的是确定含as的nachr在小鼠尼古丁奖励、依赖和戒断中的作用。静脉自我给药过程被认为是最可靠的措施，加强滥用药物的性质。在Specific Aim I中，我将通过检测野生型（WT）小鼠和a5 nAChR亚基基因（a5-/-）零突变小鼠的静脉尼古丁自我给药，来研究a5亚基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Specific Aim II中，我将通过测量尼古丁诱导的WT和a5-/-小鼠ICSS阈值的降低，研究含a5- nAChRs在调节急性给药尼古丁对脑奖励系统的刺激作用中的作用。最后，在Specific Aim III中，我将研究含as的nAChRs在WT和a5-/-小鼠自发尼古丁戒断期间奖励缺陷表达中的作用；在自发尼古丁戒断过程中，ICSS阈值的升高将作为尼古丁戒断相关奖励缺陷的衡量标准。我假设含as的nAChRs在调节尼古丁对大脑奖赏回路的作用中发挥重要作用，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尼古丁戒断相关的奖赏缺陷。总之，这些数据可能揭示尼古丁奖励、依赖和戒断背后的神经生物学机制的基本见解。重要的是，这些发现可能导致对人类戒烟和/或复发预防有效的新疗法的发展。

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.