Nicotine withdrawal and relapse: role of neuroadaptations in brain stress systems

描述（由申请人提供）：烟草成瘾是一种慢性复发性疾病，其特征是强迫性吸烟行为和停止使用烟草后的负面情感状态。吸烟与几乎所有器官的癌症都有关联，据估计，吸烟每年导致44万美国人死亡。我们实验室的研究证明了“应激”神经肽促肾上腺皮质激素释放因子（CRF）在尼古丁戒断的负性情感状态中的重要作用。此外，初步研究表明，压力引起的尼古丁寻求行为的复发至少部分是由大脑CRF和去甲肾上腺素系统的激活增加介导的。指导本研究的总体假设是，尼古丁戒断和应激诱导的尼古丁寻求行为复发的负面情感方面是由在情绪状态调节中起关键作用的大脑区域的CRF和去甲肾上腺素传递失调介导的。我们研究的目的是确定介导尼古丁戒断的情感方面和有助于尼古丁寻求行为复发的大脑部位。拟议的研究将重点关注CRF和去甲肾上腺素在扩展杏仁核（杏仁核中央核[CeA]和终纹床核[BNST]）中的作用，因为有证据表明，在这些大脑部位增加CRF和去甲肾上腺素的释放有助于消极情绪状态和复发。特异性目标1将探讨CeA和BNST中CRF1、CRF2、a2-肾上腺素能受体和¿1/2-肾上腺素能受体在尼古丁戒断相关的焦虑中的作用。大鼠颅内自我刺激模式将用于评估与尼古丁戒断相关的烦躁不安。大鼠的尼古丁戒断与脑奖励阈值升高（即脑奖励功能缺陷）有关，类似于吸烟者在戒烟时经历的烦躁不安。Specific Aim 2将探讨CeA和BNST中CRF1、CRF2、a2-肾上腺素能受体和¿1/2-肾上腺素能受体在应激诱导的尼古丁寻求行为复发中的作用。建议的研究将提供关于CRF和去甲肾上腺素在尼古丁戒断的负性情感状态和尼古丁寻求行为复发中的作用的重要信息。这些研究可能有助于开发新的和改进的药物治疗烟草成瘾。公共卫生相关性：烟草成瘾是一种慢性疾病，其特征是戒断期后的戒断和复发。拟议的实验重点是开发与尼古丁戒断和吸烟复发相关的负面情绪状态的新型非成瘾性治疗方法。这些新颖的治疗方法可能有助于提高戒烟率。

DESCRIPTION (provided by applicant): Tobacco addiction is a chronic relapsing disorder that is characterized by compulsive tobacco smoking behavior and a negative affective state upon the discontinuation of tobacco use. Smoking has been associated with cancers in nearly all organs and it has been estimated that it leads to the death of 440,000 Americans each year. Research in our laboratory has provided evidence for an important role of the "stress" neuropeptide corticotropin-releasing factor (CRF) in the negative affective state of nicotine withdrawal. In addition, preliminary studies suggest that stress-induced relapse to nicotine seeking behavior is at least partly mediated by an increased activation of brain CRF and norepinephrine systems. The overall hypothesis guiding the proposed studies is that the negative affective aspects of nicotine withdrawal and stress-induced relapse to nicotine seeking behavior are mediated by a dysregulation of CRF and norepinephrine transmission in brain areas that play a critical role in the regulation of emotional states. The aim of our studies is to identify brain sites that mediate the affective aspects of nicotine withdrawal and contribute to relapse to nicotine seeking behavior. The proposed studies will focus on the role of CRF and norepinephrine in the extended amygdala (central nucleus of the amygdala [CeA] and bed nucleus of the stria terminalis [BNST]) as evidence indicates that an increased release of CRF and norepinephrine in these brain sites contributes to negative mood states and relapse. Specific Aim 1 will explore the role of CRF1, CRF2, a2-adrenergic, and ¿1/2- adrenergic receptors in the CeA and BNST in the dysphoria associated with nicotine withdrawal. The rat intracranial self-stimulation paradigm will be used to assess the dysphoria associated with nicotine withdrawal. Nicotine withdrawal in rats is associated with elevations in brain reward thresholds (i.e., deficit in brain reward function) that are analogous to the dysphoria experienced by smokers upon a cessation attempt. Specific Aim 2 will explore the role of CRF1, CRF2, a2-adrenergic, and ¿1/2- adrenergic receptors in the CeA and BNST in stress-induced relapse to nicotine seeking behavior. The proposed studies will provide important information about the role of CRF and norepinephrine in the negative affective state of nicotine withdrawal and in relapse to nicotine seeking behavior. These studies may contribute to the development of novel and improved pharmacotherapies for tobacco addiction. PUBLIC HEALTH RELEVANCE: Tobacco addiction is a chronic disease that is characterized by withdrawal and relapse after periods of abstinence. The proposed experiments focus on the development of novel and non-addictive treatments for the negative mood state associated with nicotine withdrawal and relapse to tobacco smoking. These novel treatments may aid in improving smoking cessation rates.