Different components of nicotine-induced upregulation of nicotinic receptors

描述（由申请人提供）：在美国和世界范围内，吸烟是导致可预防死亡的主要原因。了解为什么吸烟是高度成瘾性的，并确定成瘾的潜在机制，将对开发预防成瘾所需的戒烟新疗法有巨大的好处。尼古丁是烟草中导致上瘾的主要因素。成瘾是由尼古丁与大脑中的尼古丁乙酰胆碱受体（nachr）结合引起的。高亲和性nachr，主要是大脑奖赏区的“¿4¿2”nachr，介导尼古丁的强化效应。尼古丁直接作用于nachr的唯一持久效应（即超过几分钟）是一种被称为尼古丁诱导的nachr上调（上调）的现象。我们已经证明，nAChR的上调比最初假设的要复杂得多，它由多个过程组成，这些过程以不同的速率发生，由不同的机制引起。提出的研究的一个目标是更详细地描述我们最近发现的nAChR上调的两个组成部分。在第一个目标中，我们将研究尼古丁暴露如何增加神经元和异源细胞中nAChR的内吞和¿4¿2 nAChR的再循环。在第二个目标中，我们将更详细地测试尼古丁暴露如何调节¿4¿2 nachr的糖基化。拟议研究的另一个目标是检查nAChR配体和戒烟药物如何影响上调的不同组成部分。这些实验将在第三阶段进行。

DESCRIPTION (provided by applicant): Tobacco smoking is a leading cause of preventable deaths in the United States and worldwide. Understanding why tobacco smoking is highly addictive and identifying the mechanisms underlying addiction would be of tremendous benefit in developing new therapies for smoking cessation needed for preventing addiction. Nicotine is the primary agent in tobacco leading to addiction. Addiction is initiated by nicotine binding to nicotinic acetylcholine receptors (nAChRs) in the brain. High-affinity nAChRs, mainly "¿4¿2" nAChRs in the brain's reward areas, mediate the reinforcing effects of nicotine. The only long-lasting effect, i.e., greater than a few minutes, of nicotine directly on nAChRs is a phenomenon called nicotine-induced upregulation of nAChRs (upregulation). We have demonstrated that nAChR upregulation is much more complex than originally assumed consisting of multiple processes that occur at very different rates and are caused by different mechanisms. One goal of the proposed research is to characterize in more detail the two components of nAChR upregulation that we have recently discovered. In the first Aim, we will examine how nicotine exposure increases nAChR endocytosis and recycling of ¿4¿2 nAChRs in neurons and heterologous cells. In the second Aim, we will test in more detail how nicotine exposure regulates the glycosylation of ¿4¿2 nAChRs. Another goal of the proposed research is to examine how nAChR ligands and smoking cessation agents affect the different components of upregulation. These experiments will be performed in the third Aim.