Role of Brain Nicotinic Receptors in Addiction Behaviors

吸烟已经导致了肺癌和心脏病的流行，并且是可预防的主要原因。 美国的健康状况不佳这种流行病是由于人们渴望感受尼古丁的影响，而尼古丁很可能 通过尼古丁与神经元烟碱型乙酰胆碱受体(NAChRs)的结合而介导。它的作用机制 尼古丁依赖是未知的，然而，我们发现了一个大的nAChRs家族表达在 大脑。具有A.4和(32个亚基)的nAChRs对尼古丁和慢性尼古丁暴露的亲和力最高 (吸烟)在人类吸烟者和动物模型中产生这些nAChR的增加或上调。 我们提出，长期接触尼古丁会改变大脑中nAChRs的性质，而这些变化 这是依赖的分子机制的基础。最初接触尼古丁会激活nAChRs，但会是慢性的 暴露会抑制nAChR功能(脱敏)。补偿机制(上调)是 由慢性尼古丁诱导，有可能维持正常的神经传递水平。激动剂的移除 通过戒烟可以恢复nAChRs，产生过量的活性nAChRs，这可能 有助于产生继续吸烟的生理欲望。为了验证这一假设，我们将检查 尼古丁调节高亲和力A4/|32nAChRs功能和表达的机制(S) 使用转基因小鼠的组织培养模型系统和品系。我们建议调查 用体外表达系统研究nAChR上调的分子机制(S) 结合遗传和生化方法来表征我们已经鉴定的几种蛋白质 与CX4/|32 nAChRs相互作用。我们还将探讨nAChR脱敏在诱导 通过利用几种药物的作用上调尼古丁成瘾及其对行为的影响 在cx4和[32亚基中发现的突变对受体脱敏有相反的影响，并可能 因此，以不同的方式改变受体的上调。

Cigarette use has led to an epidemic of lung cancer and heart disease and is the major preventable cause of poor health in the U.S.This epidemic is driven by the desire to feel the effects of nicotine, which are likely mediated by binding of nicotine to neuronal nicotinic acetylcholine receptors (nAChRs). The mechanisms of nicotine dependence are unknown, however, we have discovered a large family of nAChRs expressed in brain. nAChRs with a.4 and (32 subunits have the highest affinity for nicotine and chronic nicotine exposure (smoking) produces an increase, or up-regulation, of these nAChRs in human smokers and animal models. We proposed that long term nicotine exposure changes the properties of nAChRs in brain, and these changes underlie the molecular mechanism of dependence. Initial exposure to nicotine activates nAChRs, but chronic exposure depresses nAChR function (desensitization). Compensatory mechanisms (up-regulation) are induced by chronic nicotine, potentiallyto maintain normal levels of neurotransmission. Removal of agonist via smoking cessation allows recovery of nAChRs, producing an excess of active nAChRs which may contribute to the physiological desire to continue smoking. To test this hypothesis we will examine the mechanism(s) by which nicotine regulates the function and expression of the high affinity a4/|32 nAChRs using tissue culture model systems and lines of genetically altered mice. We propose to investigate the underlying molecular mechanism(s) of nAChR up-regulation using an in vitro expression system in combination with genetic and biochemical methods to characterize several proteins that we have identified that interact with cx4/|32 nAChRs. We will also explore the role of nAChR desensitization in the induction of up-regulation and its effects on behaviors related to nicotine addiction by capitalizingon the effects of several mutations identified in cx4and [32subunits which have contrasting effects on receptor desensitization and may therefore alter receptor up-regulation differently.