Alpha 5 nAChR is a Risk Factor within the Dopamine System for Nicotine Addiction

描述（由申请人提供）：全基因组关联研究在CHRNA5基因中发现了一个非同义SNP (rs16969968)，该基因编码α5烟碱受体（nAChR）亚基。这种SNP会使重度吸烟的风险增加两倍，并增加患肺癌的风险。与人类遗传学一致，我们的初步研究表明α5 nAChR在尼古丁戒断综合征的表达中是必需的。α5 nAChR还调节对尼古丁诱导行为的敏感性，并在高剂量下控制尼古丁的自我给药。在这些拟议的研究中，我们将研究α5对中脑多巴胺（DA）系统的机制作用，从而加强奖励和成瘾行为。我们将研究rs16969968 SNP对DA信号的影响，从中脑的来源到纹状体的主要目标，包括对处理奖励很重要的伏隔核（NAc）。我们的体内多电极记录显示，尼古丁增加了DA神经元的相爆放电，我们的循环伏安法和体内微透析数据显示，尼古丁诱导的DA神经元放电变化以特定靶标的方式在处理强化和奖励的区域翻译，包括NAc核心和外壳。然而，关于α5亚基或rs16969968 SNP的作用，以及α5亚基在调节靶点DA神经元放电和DA释放关系中的作用知之甚少。我们的工作假设是尼古丁通过α5-nAChR亚基在来源（即中脑的DA神经元）和目标（包括NAc和背纹状体）上调节DA信号。目的是检验尼古丁诱导的DA系统变化在慢性尼古丁暴露和戒断期间演变的假设。这项研究的意义在于预期这些尼古丁诱导的DA系统的活动和变化有助于从最初的尼古丁使用到成瘾的转变。烟草使用仍然是美国可预防性死亡的主要原因，这些研究为尼古丁成瘾和开发有助于戒烟的疗法提供了机制基础。

DESCRIPTION (provided by applicant): Genome-wide association studies identified a nonsynonymous SNP (rs16969968) within the CHRNA5 gene that encodes for the α5 nicotinic receptor (nAChR) subunit. This SNP produces a twofold higher risk for heavy smoking and increases the risk for lung cancer. Consistent with the human genetics, our preliminary studies showed that the α5 nAChR is necessary for the expression of the nicotine withdrawal syndrome. The α5 nAChR also regulates sensitive to nicotine-induced behaviors and controls nicotine self-administration at high doses. In these proposed studies, we will investigate α5's mechanistic action on the midbrain dopamine (DA) systems that reinforce rewarding and addictive behaviors. We will examine the effect of the rs16969968 SNP on DA signaling from its source in the midbrain to its main targets in the striatum, including the nucleus accumbens (NAc) which is important for processing reward. Our in vivo multi-tetrode recordings show that nicotine increases the phasic burst firing of DA neurons, and our cyclic voltammetry and in vivo microdialysis data show that nicotine-induced changes in DA neuron firing are translated in a target-specific manner in areas that process reinforcement and reward, including the NAc core and shell. However, little is known about the role of the α5 subunit or the rs16969968 SNP and about the role of the α5-subunit in regulating the relationship between DA neuron firing and DA release in targets. Our working hypothesis is that nicotine acts via the α5-nAChR subunit to modulate DA signaling both at the source (i.e., DA neurons in the midbrain) and at the targets (including the NAc and the dorsal striatum). The aims examine the hypothesis that nicotine-induced changes in the DA system evolve during chronic nicotine exposure and during the withdrawal period. The significance of the study originates from the expectation that these nicotine-induced activities and changes in the DA system contribute to the transition from initial nicotine use to addiction. Tobacco use remains the leading cause of preventable death in the United States, and these studies provide a mechanistic basis for nicotine addiction and for developing therapies to aid smoking cessation.