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

描述(申请人提供)：全基因组关联研究发现了CHRNA5基因中的一个非同义SNP(Rs16969968)，该基因编码5尼古丁受体(NAChR)亚单位。这种SNP会使重度吸烟的风险增加一倍，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，5 nAChR是尼古丁戒断综合征表达所必需的。5 nAChR还调节对尼古丁诱导的行为的敏感性，并控制高剂量的尼古丁自我给药。在这些拟议的研究中，我们将研究5‘S对加强奖赏和成瘾行为的中脑多巴胺(DA)系统的机械作用。我们将研究rs16969968 SNP对从它在中脑的来源到它在纹状体的主要目标的DA信号的影响，包括对处理奖赏非常重要的伏隔核(NAC)。我们在体内的多路四极管记录显示，尼古丁增加了DA神经元的相位爆发式放电，我们的循环伏安和体内微透析数据表明，尼古丁诱导的DA神经元放电的变化在处理强化和奖励的区域，包括NAC核心和外壳，以靶向特异性的方式翻译。然而，关于5亚基或rs16969968 SNP的作用，以及5亚基在调节DA神经元放电和靶区DA释放之间的关系方面所起的作用，人们知之甚少。我们的工作假设是，尼古丁通过5-nAChR亚基作用，在来源(即中脑中的DA神经元)和目标(包括NAC和背侧纹状体)调节DA信号。这些研究的目的是检验一种假说，即尼古丁引起的DA系统的变化在长期尼古丁暴露和戒断期间发生变化。这项研究的意义源于这样一种预期，即这些尼古丁诱导的活动和DA系统的变化有助于从最初的尼古丁使用过渡到成瘾。在美国，烟草使用仍然是可预防的死亡的主要原因，这些研究为尼古丁成瘾提供了机制基础，并为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 ¿5 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 ¿5 nAChR is necessary for the expression of the nicotine withdrawal syndrome. The ¿5 nAChR also regulates sensitive to nicotine-induced behaviors and controls nicotine self-administration at high doses. In these proposed studies, we will investigate ¿5'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 ¿5 subunit or the rs16969968 SNP and about the role of the ¿5-subunit in regulating the relationship between DA neuron firing and DA release in targets. Our working hypothesis is that nicotine acts via the ¿5-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.