Central mechanisms of nicotine reinforcement and dependence

项目总结/摘要 烟草使用仍然是美国的一个主要公共卫生问题， 使用者变得依赖，吸烟是美国主要的可避免死亡原因。 目前的建议集中在动物研究，以调查神经生物学机制，介导 尼古丁成瘾增加静脉内自我给予尼古丁至 依赖性已经发展，并将进一步完善，验证和比较急性强化 模型初步结果表明，CRF-1拮抗剂可以阻断焦虑样反应， 与急性尼古丁戒断和尼古丁引起的尼古丁反应增加有关 在扩展访问模式中的剥夺。本提案的总体假设是， 在长期接触（尼古丁依赖）动物中，尼古丁的寻求部分是由 下丘脑外促肾上腺皮质激素释放因子（CRF）应激系统和相关应激调节剂 基底前脑的特定区域（延伸杏仁核）。为了检验这一假设，有三个具体目标： 建议：1）。验证大鼠尼古丁自我给药的扩展依赖模型。2）。探讨 焦虑样状态下特定神经化学系统内的神经药理学机制 尼古丁戒断3）。探讨脑内特定部位的神经药理学机制， 延长杏仁核对依赖大鼠尼古丁自我给药的影响。静脉注射自体免疫动物模型 给药、焦虑样反应和脑刺激奖励结合生化研究，以及 将采用特定神经药理学试剂的全身和脑内微量注射。项目叙述 拟议的神经生物学研究将提供关键信息，不仅为一个主要的病因， 一旦依赖继续吸烟的动机成分，有助于识别那些个体差异 这可能导致依赖性的脆弱性，并为未来的药物开发提供关键目标， 尼古丁依赖的治疗

PROJECT SUMMARY/ABSTRACT 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. PROJECT NARRATIVE 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.