The Role of Nicotinic Receptors in Nicotine Withdrawal

描述（由申请人提供）：尼古丁成瘾是世界上可预防死亡的主要原因之一。戒烟后出现的戒断症状是试图戒烟的人复吸率高的原因。因此，深入了解尼古丁戒断的机制可能会导致更好的靶向药物治疗，以帮助成功戒烟。尼古丁靶向并激活神经元烟碱乙酰胆碱受体（nAChR），即通常由内源性神经递质乙酰胆碱激活的配体门控阳离子通道。啮齿动物模型的尼古丁依赖和戒断导致更好地了解尼古丁成瘾，但具体的nAChR亚型参与戒断症状没有完全阐明。与人类吸烟者一样，长期暴露于尼古丁的啮齿动物在停药后表现出躯体（身体）和情感戒断症状。虽然躯体症状具有外周成分，但情感症状是中枢介导的，并且与中脑奖赏和运动回路中的多巴胺能神经元的活动减退有关。最近，有证据表明，躯体和情感尼古丁戒断症状可能依赖于不同的和单独的nAChR亚型的慢性激活。先前的工作表明，含有α 4亚基（α 4 *）的nAChR对于尼古丁奖赏和耐受是必要和充分的，但它们在戒断中所起的作用尚不清楚。在本申请中测试的假设是α 4 * nAChR的激活对于情感性尼古丁戒断症状而不是躯体性尼古丁戒断症状是必要且充分的。为了确定α 4 * nAChR表达是否是躯体和/或情感戒断症状所必需的，不表达α 4 * nAChR的敲除小鼠将用尼古丁长期治疗，并且情感和躯体戒断症状将在药物停止后测量，并与尼古丁戒断的野生型（WT）动物进行比较。在目标2中，表达过敏性α 4 * nAChR的小鼠将长期暴露于选择性激活突变受体的小剂量尼古丁。将在停止后测量情感和躯体戒断症状，并与WT小鼠进行比较。总之，这项研究的结果应该对尼古丁戒断的分子基础产生有价值的见解。公共卫生相关性：戒烟后出现的戒断症状是试图戒烟的人复吸率高的原因。拟议项目的目标是确定以前与尼古丁的急性成瘾特性相关的神经元烟碱乙酰胆碱受体亚型是否也参与与戒烟相关的戒断症状。这项研究的结果应该对尼古丁戒断的分子基础产生有价值的见解。

DESCRIPTION (provided by applicant): Nicotine addiction is one of the primary causes of preventable mortality in the world. Withdrawal symptoms that occur after nicotine cessation account for the high incidence of relapse in people attempting to quit smoking. Thus, insight into the mechanism of nicotine withdrawal could lead to better targeted pharmacotherapy to aid in successful smoking cessation. Nicotine targets and activates neuronal nicotinic acetylcholine receptors (nAChRs), ligand gated cation channels that are normally activated by the endogenous neurotransmitter, acetylcholine. Rodent models of nicotine dependence and withdrawal have lead to a better understanding of nicotine addiction; however the specific nAChR subtypes involved in withdrawal symptoms are not fully elucidated. As in human smokers, rodents exposed to chronic nicotine exhibit somatic (physical) and affective withdrawal symptoms after drug cessation. While somatic symptoms have a peripheral component, affective symptoms are centrally mediated and associated with hypoactivity of dopaminergic neurons in midbrain reward and locomotor circuits. Recently, there is evidence that somatic and affective nicotine withdrawal symptoms may be dependent on chronic activation of distinct and separate nAChR subtypes. Previous work indicates that a4 subunit-containing (a4*) nAChRs are both necessary and sufficient for nicotine reward and tolerance, but the role they play in withdrawal is unknown. The hypothesis being tested in this application is that activation of a4* nAChRs is necessary and sufficient for affective, but not somatic nicotine withdrawal symptoms. To determine if a4* nAChR expression is necessary for somatic and/or affective withdrawal symptoms, knockout mice that do not express a4* nAChRs will be chronically treated with nicotine and both affective and somatic withdrawal symptoms will be measured upon drug cessation and compared to nicotine withdrawn wild-type (WT) animals. In Aim 2, mice expressing hypersensitive a4* nAChRs will be chronically exposed to small doses of nicotine that selectively activate the mutant receptor. Affective and somatic withdrawal symptoms will be measured upon cessation and compared to WT mice. Together, the results from this study should yield valuable insight into the molecular underpinnings of nicotine withdrawal. PUBLIC HEALTH RELEVANCE: Withdrawal symptoms that occur after nicotine cessation account for the high incidence of relapse in people attempting to quit smoking. The goal of the proposed project is to determine if a neuronal nicotinic acetylcholine receptor subtype previously linked to the acute, addictive properties of nicotine is also involved in withdrawal symptoms associated with smoking cessation. The results of this study should yield valuable insight into the molecular underpinnings of nicotine withdrawal.