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。这种习惯不仅会损害人的健康 个人用户以及他们周围的人（二手烟）。尼古丁是主要成瘾物质 烟草的组成部分，人们付出了巨大的努力来了解其主要的增强作用和 主要刺激效应包括奖励、镇痛和精神运动激活等。 尽管尼古丁是一种非常温和的强化剂，但仍有越来越多的人使用烟草但无法戒烟 产品，然后是所有滥用非法物质的人。这表明除了尼古丁的增强作用 影响 一些其他过程可能会导致尼古丁依赖。研究人员和实践者是 越来越意识到某些形式的联想学习与理解药物使用特别相关 和虐待。吸烟者在存在大量有益刺激（如食物、 酒精、工作刹车或同伴互动等等。研究学习背后的神经基质 如果目标是，尼古丁刺激与其他奖励相关的机制非常重要 使用聚合证据方法制定更有效的治疗策略。开始填写这个 我们对尼古丁刺激联想学习所涉及的神经基质的理解存在显着差距， 我们将跟进初步研究表明，背内侧尾壳核的前部和后部 不同程度地参与尼古丁学习的早期和晚期阶段。因为尾壳核是 基底神经节的组成部分，具有来自皮质区域的广泛输入和显着的抑制输出 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。因此研究 本申请中提出的建议将以编程方式建立在我们之前的发现的基础上，通过更仔细地检查 背内侧尾壳核前部和后部及其传出和传入的功能参与 联想学习与尼古丁刺激的联系。为此，我们将使用翻译相关的 静脉输注模型和尼古丁自我给药模型，其中尼古丁输注与 获得液体蔗糖。这些模型产生了对尼古丁-蔗糖关联的强大学习，揭示为 静脉注射尼古丁后，勺子入口升高。以高水平靶向感兴趣的途径 精确度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 CRE 依赖性腺相关病毒 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取和表达 尼古丁刺激。从这些实验中获得的知识将填补我们理解的一个重要空白 神经通路可能导致烟草依赖的顽固性。