Central mechanisms of nicotine reinforcement and dependence

尼古丁强化和依赖的中心机制

• 批准号: 7467212
• 负责人: George F. Koob
• 金额: $ 37.9万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-05 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7467212
• 关键词: Acute; Agonist; Amygdaloid structure; Animal Model; Animals; Anxiety; Biochemical; Biological; Brain; Cause of Death; Corticotropin-Releasing Hormone; Dependence; Development; Drug Addiction; Environment; Etiology; Future; Individual Differences; Intake; Intravenous; Lead; Mediating; Microinjections; Modeling; Motivation; Neurobiology; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Pharmaceutical Preparations; Pharmacology; Procedures; Psychological reinforcement; Public Health; Rattus; Rewards; Self Administration; Site; Smoke; Stress; System; Testing; Tobacco smoking; Tobacco use; United States; basal forebrain; base; deprivation; heuristics; innovation; insight; neurobiological mechanism; neurochemistry; neuropeptide Y; response; therapy development; translational study

DESCRIPTION (provided by applicant): Tobacco use continues to be a major public health problem in the United States with approximately one-third of users becoming dependent and tobacco smoking is the leading avoidable cause of death in the United States. The present proposal focuses on animal studies to investigate neurobiological mechanisms that mediate nicotine addiction. An animal model of increased intravenous self-administration of nicotine to the point of dependence has been developed and will be further refined, validated and compared to acute reinforcement models. Preliminary results show that a CRF-1 antagonist can block both the anxiety-like responses associated with acute nicotine withdrawal and the increase in nicotine responding produced by nicotine deprivation in an extended access model. The overall hypothesis of the present proposal is that enhanced nicotine seeking in extended access (nicotine-dependent) animals is in part produced by an overactivity of extrahypothalamic corticotropin-releasing factor (CRF) stress systems and related stress modulatory agents in specific regions of the basal forebrain (extended amygdala). To test this hypothesis, three specific aims are proposed: 1). To validate an extended dependence model of nicotine self-administration in rats. 2). To explore the neuropharmacological mechanisms within specific neurochemical systems in the anxiety-like state of nicotine withdrawal. 3). To explore the neuropharmacological mechanisms within specific sites within the extended amygdala on nicotine self-administration in dependent rats. Animal models of intravenous self- administration, anxiety-like responses, and brain stimulation reward combined with biochemical studies, and systemic and intracerebral microinjections of specific neuropharmacological agents will be employed. PUBLIC HEALTH RELEVANCE The proposed neurobiological studies will provide key information not only for the etiology of a major component of the motivation to continue to smoke once dependent, help identify those individual differences that may lead to vulnerability to dependence, and provide key targets for future medications development for the treatment of nicotine dependence.

描述（由申请人提供）：烟草使用仍然是美国的一个主要公共卫生问题，大约三分之一的使用者变得依赖烟草，吸烟是美国主要的可避免的死亡原因。目前的提案侧重于动物研究，以调查介导尼古丁成瘾的神经生物学机制。已经开发出一种增加静脉自我注射尼古丁至依赖点的动物模型，并将进一步完善、验证并与急性强化模型进行比较。初步结果表明，CRF-1 拮抗剂可以阻断与急性尼古丁戒断相关的焦虑样反应，以及在长期接触模型中尼古丁剥夺所产生的尼古丁反应增加。本提案的总体假设是，长期接触（尼古丁依赖）动物对尼古丁的寻求增强部分是由下丘脑外促肾上腺皮质激素释放因子（CRF）应激系统和基底前脑（扩展杏仁核）特定区域的相关应激调节剂的过度活跃引起的。为了检验这一假设，提出了三个具体目标：1）。验证大鼠自我给药尼古丁的扩展依赖模型。 2）。探讨尼古丁戒断焦虑样状态下特定神经化学系统内的神经药理学机制。 3）。探讨扩展杏仁核内特定位点对依赖性大鼠尼古丁自我给药的神经药理学机制。将采用静脉自我给药、焦虑样反应和脑刺激奖励与生化研究相结合的动物模型，以及特定神经药理学药物的全身和脑内显微注射。公共健康相关性拟议的神经生物学研究不仅将提供关键信息，不仅为一旦成瘾后继续吸烟的动机的主要组成部分的病因学提供关键信息，帮助识别可能导致依赖的个体差异，并为未来治疗尼古丁依赖的药物开发提供关键目标。