Central mechanisms of nicotine reinforcement and 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成为依赖者，吸烟是美国可避免的主要死因。目前的建议侧重于动物研究，以调查介导尼古丁成瘾的神经生物学机制。已经开发了一种增加尼古丁静脉自我给药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和延长使用模型中尼古丁剥夺产生的尼古丁反应增加。本建议的总体假设是，增强尼古丁寻求在扩展访问（尼古丁依赖）的动物部分是由过度活动的下丘脑外促肾上腺皮质激素释放因子（CRF）的压力系统和相关的压力调节剂在特定区域的基底前脑（扩展杏仁核）。为了验证这一假设，提出了三个具体目标：1）。验证大鼠尼古丁自我给药的扩展依赖模型。2）。探讨尼古丁戒断焦虑样状态下特定神经化学系统的神经药理学机制。3）。探讨尼古丁依赖大鼠杏仁核内特定部位对尼古丁自我给药的神经药理学机制。将采用静脉内自我给药、焦虑样反应和脑刺激奖励结合生化研究以及全身和脑内微量注射特定神经药理学药物的动物模型。公共卫生相关性拟议的神经生物学研究将提供关键信息，不仅是一个主要组成部分的动机，继续吸烟，一旦依赖的病因，帮助确定那些个体差异，可能导致依赖的脆弱性，并提供关键目标，为未来的药物开发治疗尼古丁依赖。

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.