Central mechanisms of nicotine reinforcement and dependence

项目摘要/摘要 烟草使用在美国仍然是一个主要的公共健康问题，大约三分之一的人 在美国，吸烟者变得依赖和吸烟是主要的可避免的死亡原因。 目前的建议侧重于动物研究，以探讨神经生物学机制 尼古丁成瘾。尼古丁静脉自身给药增加到一定程度的动物模型 依赖已经形成，并将被进一步提炼、验证，并与急性强化进行比较 模特们。初步结果表明，CRF-1拮抗剂可以阻断这两种焦虑样反应 与急性尼古丁戒断和尼古丁产生的尼古丁反应增加有关 扩展访问模型中的剥夺。本提案的总体假设是，增强 长期接触(尼古丁依赖)动物寻求尼古丁的部分原因是 大鼠下丘脑外促肾上腺皮质激素释放因子应激系统及相关应激调节剂的研究 基底前脑的特定区域(延伸的杏仁核)。为了验证这一假设，有三个具体目标 建议：1)。目的：验证大鼠尼古丁自我给药的长期依赖模型。2)。去探索 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)。探索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。静脉自体输液动物模型的建立 给药、焦虑样反应、脑刺激奖励与生化研究相结合，以及 将采用全身和脑内微量注射特定的神经药理药物。项目叙事 拟议的神经生物学研究将不仅为重大疾病的病因提供关键信息。 继续吸烟的动机的组成部分，一旦依赖，有助于识别这些个体差异 这可能会导致易受依赖，并为未来的药物开发提供关键的靶点 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.