Neural Pathways Underlying Learning with Nicotine Stimulus

尼古丁刺激学习的神经通路

• 批准号: 9211721
• 负责人: Sergios Charntikov
• 金额: $ 22.49万
• 依托单位: UNIVERSITY OF NEW HAMPSHIRE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9211721
• 关键词: Absence of pain sensation; Abstinence; Accidents; Acquired Immunodeficiency Syndrome; Affect; Afferent Pathways; Alcohols; Anterior; Area; Awareness; Basal Ganglia; Behavior; Behavioral; Biomedical Engineering; Canine Adenoviruses; Cells; Cessation of life; Complex; Coupling; Dependovirus; Desire for food; Drug abuse; Drug usage; Efferent Pathways; Enterobacteria phage P1 Cre recombinase; Environment; Environmental Tobacco Smoke; Event; Food; Future; Globus Pallidus; Goals; Habits; Healthcare; Individual; Infusion procedures; Intravenous; Intravenous infusion procedures; Knowledge; Learning; Legal; Liquid substance; Mediating; Midbrain structure; Modeling; Murder; Names; National Institute of Drug Abuse; Neural Pathways; Neurobiology; Nicotine; Nicotine Dependence; Organism; Outcome; Output; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Process; Productivity; Property; Rattus; Relapse; Research; Research Personnel; Rewards; Rodent; Role; Self Administration; Series; Site; Smoker; Stimulus; Substantia nigra structure; Sucrose; Suicide; Tobacco; Tobacco Dependence; Tobacco use; Viral; Work; addiction; behavioral pharmacology; classical conditioning; conditioning; design; economic impact; experience; experimental study; follow-up; insight; interest; killings; neurobiological mechanism; peer; putamen; reinforcer; relating to nervous system; response; social; theories; treatment strategy

Tobacco use is the leading cause of preventable deaths worldwide. This habit is not only debilitating to individual users but also to those around them (second-hand smoking). Nicotine is the primary addictive component of tobacco and there have been a significant effort to understand its primary reinforcing and primary stimulus effects that include reward, analgesia, and psychomotor activation among many others. Despite the fact that nicotine is a very mild reinforcer, there are more people using and unable to quit tobacco products then all of those abusing illicit substances. This indicates that in addition to nicotine's reinforcing effects some other processes likely contribute to nicotine dependence. Researchers and practitioners are increasingly aware that some forms of associative learning are particularly relevant to understanding drug use and abuse. Smokers experience nicotine state in a presence of abundantly present rewarding stimuli like food, alcohol, work brakes, or peer interaction to name a few. Investigating neural substrates underlying learning mechanisms with nicotine stimulus associated with other rewards is of great importance if the goal is to develop more efficacious treatment strategies using a converging evidence approach. To start filling this significant gap in our understanding of neural substrates involved in associative learning with nicotine stimulus, we will follow-up on the preliminary studies showing that anterior and posterior dorsomedial caudate-putamen are differentially involved in early and late stages of learning with nicotine. Because caudate-putamen is an integral part of the basal ganglia, with extensive input from cortical areas and prominent inhibitory output to pallidum and substantia nigra, we hypothesize that the afferent and efferent pathways connecting to dorsomedial caudate-putamen are critical for associative learning with nicotine stimulus. Thus the research proposed in this application will programmatically build on our previous findings by examining more closely the functional involvement of anterior and posterior dorsomedial caudate-putamen and their efferent and afferent connections in associative learning with nicotine stimulus. To do so we will use translationally relevant intravenous infusion model and nicotine self-administration model where nicotine infusions are paired with access to liquid sucrose. These models produce robust learning of nicotine-sucrose association revealed as elevated dipper entries following intravenous nicotine infusion. To target pathways of interest with high level of precision we will use double viral approach which includes an infusion of CRE-recombinase expressing canine adenovirus-2 into the areas with neural terminals and an infusion of CRE-dependent adeno-associated virus into the area where cell bodies are located. We hypothesize that inhibiting afferent and efferent pathways connecting to dorsomedial caudate-putamen will inhibit acquisition and expression of associative learning with nicotine stimulus. Knowledge gained from these experiments will fill an important gap in our understanding of neural pathways potentially contributing to the tenacity of tobacco dependence.

烟草使用是全世界可预防死亡的主要原因。这个习惯不仅会使人虚弱 不仅对个人吸烟者，而且对他们周围的人(二手烟)。尼古丁是主要的成瘾物质。 烟草的主要成分，人们一直在努力了解它的主要强化和 主要刺激作用包括奖励、止痛和精神运动激活等。 尽管尼古丁是一种非常温和的增强剂，但仍有更多的人使用并无法戒烟 然后是所有那些滥用非法物质的产品。这表明除了尼古丁的强化 其他一些过程可能会导致尼古丁依赖。研究人员和实践者 越来越意识到，某些形式的联想学习与了解药物使用特别相关 和虐待。吸烟者在食物等大量存在的有益刺激下体验尼古丁状态， 酒精、刹车或同伴互动等等。学习的神经基础研究 尼古丁刺激与其他奖励相关的机制非常重要，如果目标是 使用融合证据的方法制定更有效的治疗策略。开始填满这个 在我们对涉及尼古丁刺激的联想学习的神经底物的理解上存在显著差距， 我们将跟进初步研究显示，前和后背内侧尾壳核 不同程度地参与尼古丁学习的早期和后期阶段。因为尾壳核是一种 基底神经节的组成部分，有来自皮质区的广泛输入和显著的抑制输出 苍白球和黑质，我们假设传入和传出通路连接到 背内侧尾壳核对于尼古丁刺激的联想学习至关重要。因此，这项研究 在本应用程序中提出的将以编程方式基于我们以前的发现，通过更仔细地检查 前后背内侧尾壳核及其传出和传出的功能受累 联想学习与尼古丁刺激的联系。为此，我们将使用与翻译相关的 静脉输注模式和尼古丁自我给药模式，其中尼古丁输注与 获取液体蔗糖的途径。这些模型产生了尼古丁-蔗糖关联的稳健学习，显示为 静脉注射尼古丁后，勺子进入升高。以高水平的 我们将使用双病毒方法，其中包括输注表达Cre重组酶的犬 腺病毒-2进入神经末梢区域并输注依赖Cre的腺相关病毒 进入细胞体所在的区域。我们假设抑制传入和传出通路 连接到背内侧尾壳核将抑制联想学习的获得和表达 尼古丁刺激物。从这些实验中获得的知识将填补我们在理解 神经通路可能有助于烟草依赖的顽固性。