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

描述(申请人提供)：烟草成瘾是一种慢性复吸障碍，其特征是强制吸烟行为和停止使用烟草后的负面情感状态。吸烟几乎与所有器官的癌症有关，据估计，每年有44万美国人死于吸烟。我们实验室的研究表明，“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绪状态中起着重要作用。此外，初步研究表明，压力导致的尼古丁寻求行为复发至少部分是通过大脑CRF和去甲肾上腺素系统的激活来调节的。指导这项研究的总体假设是，尼古丁戒断和应激导致的尼古丁寻求行为复发的负面情感方面是由CRF和去甲肾上腺素在大脑区域的调节失调所介导的，这些区域在情绪状态的调节中起着关键作用。我们研究的目的是确定大脑中调节尼古丁戒断的情感方面并有助于尼古丁寻求行为复发的大脑部位。拟议的研究将集中在延伸的杏仁核(杏仁中央核[CEA]和终纹床核[BNST])中CRF和去甲肾上腺素的作用，作为证据表明这些脑区CRF和去甲肾上腺素的释放增加导致负面情绪状态和复发。具体目标1将探讨CRF1、CRF2、α2-肾上腺素能和β1/2-肾上腺素能受体在尼古丁戒断相关焦虑症中的作用。大鼠颅内自我刺激范式将被用来评估与尼古丁戒断相关的烦躁不安。大鼠的尼古丁戒断与大脑奖励阈值(即大脑奖励功能缺陷)的升高有关，这类似于吸烟者在尝试戒烟时所经历的焦虑症。特定目的2将探讨CEA和BNST中CRF1、CRF2、α2-肾上腺素能和β1/2-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。建议的研究将提供有关CRF和去甲肾上腺素在尼古丁戒断的负面情感状态和复吸尼古丁寻求行为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治疗烟草成瘾的药物疗法。与公共卫生相关：烟草成瘾是一种慢性疾病，其特征是戒烟一段时间后戒断并复发。拟议的实验重点是开发新的和非成瘾的治疗方法，以治疗与尼古丁戒断和吸烟复发相关的负面情绪状态。这些新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.