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

尼古丁戒断和复发：神经适应在大脑应激系统中的作用

• 批准号: 8049235
• 负责人: Adriaan Willem Bruijnzeel
• 金额: $ 28.14万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049235
• 关键词: Abbreviations; Abstinence; Adrenergic Agents; Adrenergic Receptor; Affective; Affective Symptoms; American; Amygdaloid structure; Applications Grants; Area; Behavior; Brain; CRF receptor type 1; CRF receptor type 2; Cell Nucleus; Cerebrospinal Fluid; Cessation of life; Chronic; Chronic Disease; Conflict (Psychology); Corticotropin-Releasing Hormone; Development; Disease; Electric Stimulation; Emotional; Exposure to; Gold; Health; High Pressure Liquid Chromatography; Homovanillic Acid; Hour; Human; Hypothalamic structure; Intraventricular; Laboratories; Lateral; Malignant Neoplasms; Measures; Mediating; Methoxyhydroxyphenylglycol; Modeling; Neurons; Neuropeptides; Nicotine; Nicotine Withdrawal; Nicotinic Receptors; Norepinephrine; Organ; Pharmaceutical Preparations; Pharmacotherapy; Pituitary-Adrenal System; Play; Procedures; Rattus; Regulation; Relapse; Reporting; Research; Rewards; Role; Self Stimulation; Signal Transduction; Site; Smoker; Smoking; Stress; Structure of terminal stria nuclei of preoptic region; System; Tobacco Dependence; Tobacco smoking; Tobacco smoking behavior; Tobacco use; Withdrawal; adrenergic; base; craving; drug seeking behavior; drug withdrawal; dysphoria; experience; footshock induced; improved; intraperitoneal; negative mood; neuroadaptation; neurobehavioral; noradrenergic; norepinephrine system; novel; prevent; receptor; research study; smoking cessation; subcutaneous; transmission process

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.

描述（由适用提供）：烟草成瘾是一种慢性继电器障碍，其特征是强迫烟草吸烟行为和在停用烟草使用时受到负面影响的状态。吸烟与几乎所有器官的癌症有关，据估计，它每年导致440,000名美国人死亡。我们实验室的研究提供了证据，证明了尼古丁戒断状态的“应激”神经肽皮质激素释放因子（CRF）的重要作用。此外，初步研究表明，压力引起的对尼古丁寻求行为的缓解至少部分是由于脑CRF和去甲肾上腺素系统的激活增加而介导的。指导拟议的研究的总体假设是，尼古丁戒断和应激引起的对尼古丁寻求行为的缓解的负面影响是通过在大脑区域的CRF和去甲肾上腺素传播的失调来介导的，在对情绪状态的调节中起着至关重要的作用。我们研究的目的是确定介导尼古丁戒断的情感方面的大脑部位，并为尼古丁寻求行为做出贡献。拟议的研究将重点介绍CRF和去甲肾上腺素在扩展的杏仁核（杏仁核的中央核[CEA]和质谱末端的床核[BNST]）中，因为证据表明，CRF和去甲肾上腺素的释放增加了这些大脑现场的释放，对负面情绪状态有助于消极情绪状态。具体目标1将探索CRF​​1，CRF2，A2-肾上腺素和1/2-在CEA和BNST中的肾上腺肾上腺肾上腺素的作用。大鼠颅内自刺激范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大脑奖励阈值的高程（即脑奖励功能的缺陷）相似，这些阈值类似于吸烟者在停止尝试时经历的烦躁不安。具体目标2将探讨CRF1，CRF2，A2-肾上腺素能和€1/2- CEA中的1/2-肾上腺素受体在压力引起的疾病寻求行为中的压力引起的缓解中的作用。拟议的研究将提供有关CRF和去甲肾上腺素在受影响的尼古丁戒断状态以及缓解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烟草成瘾药物疗法。公共卫生相关性：烟草成瘾是一种慢性疾病，其特征是禁欲后戒断和继电器。提出的实验集中于开发与尼古丁戒断和缓解烟草吸烟有关的负面情绪状态的新颖和非依恋治疗方法。这些新颖的治疗方法可能有助于提高戒烟率。