Central mechanisms of nicotine reinforcement and dependence

描述(由申请人提供)：烟草使用在美国仍然是一个主要的公共健康问题，大约三分之一的吸烟者变得依赖，吸烟是美国主要的可避免的死亡原因。目前的建议侧重于动物研究，以研究调节尼古丁成瘾的神经生物学机制。已经建立了一种动物模型，将尼古丁静脉内自身给药增加到依赖程度，并将进一步改进、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，以及在延长接触模型中尼古丁剥夺所产生的尼古丁反应的增加。本研究的总体假设是，长期接触(尼古丁依赖)动物寻求尼古丁的增强部分是由于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在基底前脑(扩大的杏仁核)的特定区域过度活跃所产生的。为了验证这一假设，本文提出了三个具体目标：1)。目的：验证大鼠尼古丁自我给药的长期依赖模型。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)。目的：探讨杏仁核特定部位对依赖大鼠尼古丁自我给药的神经药理学机制。将采用静脉给药、焦虑样反应和脑刺激奖励的动物模型，并结合生化研究，以及全身和脑内微量注射特定的神经药物。公共卫生相关性拟议的神经生物学研究将不仅为一旦依赖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，帮助确定可能导致依赖易感性的个体差异，并为未来治疗尼古丁依赖的药物开发提供关键目标。

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.