Nicotine Exposure: Molecular to Behavioral Consequences

描述（由申请人提供）：烟草使用在美国和国外仍然是一个主要的公共卫生问题，它是引发疾病导致可预防死亡的主要因素。然而，尽管有这些不良后果，全世界吸烟者的人数仍在继续增加。尽管在阐明烟草的活性成分尼古丁的几种影响的神经机制方面取得了相当大的进展，但迄今积累的知识还不足以成功地进行干预以减少烟草使用。本项目提出的实验将采用多学科方法来评估反复暴露于尼古丁对尼古丁乙酰胆碱受体（nachr）、神经元兴奋性和行为的影响。他们的共同目标是最终了解尼古丁如何启动自我给药行为，以及反复接触尼古丁如何产生促进这些行为持续表达的变化。尼古丁通过激活大脑nachr来产生对动机行为的影响。因此，尼古丁对这些受体的调节能力可以对这种药物在随后再次接触它的动物中引发这种行为的能力产生实质性的影响。项目1旨在确定尼古丁诱导的nachr上调的分子机制，并在尼古丁暴露大鼠的不同脑区描述这一现象。与其他滥用药物一样，尼古丁的使用在很大程度上依赖于它增加中脑多巴胺传递的能力。项目2将描述先前暴露于尼古丁对进入这些多巴胺系统的nachr功能特性的影响，并评估它们对多巴胺细胞突触长期增强的贡献。众所周知，反复接触尼古丁会导致运动致敏，但人们对这种效应是如何产生的知之甚少。项目3将确定涉及的脑nAChR区域，描述它们在诱导多巴胺神经元反应敏化中的作用，并确定它们的重复激活是否会导致自我使用尼古丁的动机增加。

DESCRIPTION (provided by applicant): Tobacco use remains a major public health concern in the United States and abroad where it is a major factor in the initiation of illnesses leading to preventable death. Yet, despite such adverse consequences, the number of smokers continues to increase worldwide. Although considerable progress has been made in elucidating the neuronal mechanisms underlying several of the effects of nicotine, the active component of tobacco, the knowledge accumulated to date falls short of what is necessary to intervene successfully to reduce tobacco use. The experiments proposed in this program project will use a multi-disciplinary approach to assess the impact of repeated exposure to nicotine on nicotinic acetylcholine receptors (nAChRs), neuronal excitability and behavior. They have in common the goal of ultimately understanding how nicotine acts to initiate self-administration behaviors and how repeated exposure to nicotine produces changes that promote the continued expression of these behaviors. Nicotine produces its effects on motivated behavior by activating brain nAChRs. The ability of nicotine to up regulate these receptors can thus have a substantial impact on the ability of this drug to initiate such behaviors in animals subsequently re-exposed to it. Project 1 will aim to identify the molecular mechanisms underlying nicotine-induced up regulation of nAChRs and characterize this phenomenon in different brain regions of nicotine-exposed rats. As with other drugs of abuse, nicotine use relies in large part on its ability to increase midbrain dopamine transmission. Project 2 will characterize the effect of previous exposure to nicotine on the functional properties of nAChRs with access to these dopamine systems and assess their contribution to long-term potentiation of synapses onto dopamine cells. Repeated exposure to nicotine is known to lead to locomotor sensitization, yet little is known about how this effect is produced. Project 3 will identify the brain nAChR fields involved, characterize their role in the induction of sensitization of dopamine neuron reactivity and determine whether their repeated activation leads to increased motivation to self-administer nicotine.