Neurobiological mechanisms of nicotine reinforcement: Role of the nucleus tractus

尼古丁强化的神经生物学机制：束核的作用

• 批准号: 8205369
• 负责人: Luis Miguel Tuesta
• 金额: $ 2.88万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-16 至 2013-07-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8205369
• 关键词: 15q25; Acute; Brain; Brain region; Cell Nucleus; Cessation of life; Chromosomes; Data; Developed Countries; Development; Disease; Drosophila acetylcholine receptor alpha-subunit; Efferent Pathways; Gene Cluster; Gene Targeting; Gene Transfer; Genetic; Genetic Variation; Goals; Habits; Health; Health Care Costs; Injection of therapeutic agent; Intake; Intravenous; Ion Channel; Knockout Mice; Lidocaine; Mediating; Motivation; Mus; Neurobiology; Neurons; Neuropeptides; Nicotine; Nicotine Dependence; Nicotinic Receptors; Norepinephrine; Nucleus solitarius; Opiates; Pattern; Pharmaceutical Preparations; Play; Procedures; Process; Property; Psychological reinforcement; Rattus; Regulation; Research Proposals; Respiration; Rewards; Risk; Role; Self Administration; Self Stimulation; Self-Administered; Smoking Behavior; Stress; System; Techniques; Technology; Testing; Tobacco; Tobacco Dependence; Tobacco smoke; Tobacco smoking; United States; Viral; addiction; cigarette smoking; drug reinforcement; feeding; glucagon-like peptide; glucagon-like peptide 1; in vivo; innovation; knockout gene; neurobiological mechanism; neurochemistry; novel therapeutics; receptor; research study; response; smoking cessation; subcutaneous; transmission process

DESCRIPTION (provided by applicant): Neurobiological mechanisms of nicotine reinforcement: Role of the nucleus tractus solitarius (NTS) Cigarette smoking is a principal cause of preventable death and disease in developed nations, with approximately $160 billion being spent yearly in the United States to cover direct health care costs from resulting diseases. Nicotine is the major psychoactive component of tobacco smoke responsible for tobacco addiction. Nicotine acts in the brain by stimulating nicotinic acetylcholine receptors (nAChRs), which are pentameric ion channels comprised of five discrete subunits. A major advance in our understanding of smoking behavior is the recent finding that genetic variation in the a3/ a5/¿4 nAChR subunit gene cluster on chromosome region 15q25 dramatically increases risk of tobacco addiction. Intriguingly, a3/ a5/¿4 nAChR subunits have a highly-restricted expression pattern in the brain, with the nucleus of the solitary tract (NTS) being one of the only brain regions to display robust expression of all three subunits. The NTS is involved in the regulation of feeding, respiration, processing of interoceptive information, and was recently implicated in opiate reward, yet its role in nicotine reinforcement remains largely unexplored. Preliminary data show that lidocaine-mediated NTS inactivation significantly reduces intravenous nicotine self-administration (IVSA) in rats. Furthermore, glucagon-like peptide-1 (GLP-1), a neuropeptide involved in regulating interoceptive stress and feeding inhibition, is produced in the NTS and represents one of its major efferent systems, projecting to brain regions related to drug reinforcement. Preliminary data show that GLP-1 neurons in the NTS are activated in response to acute nicotine injections. In addition, preliminary studies suggest that nicotine IVSA is almost completely abolished in mice lacking expression of the GLP-1 receptor. Taken together, these results suggest a regulatory role for the NTS, and perhaps GLP-1 transmission, in nicotine reinforcement. We aim to characterize the role of a3/ a5, and/or ¿4 -containing nAChRs in the NTS in nicotine reinforcement and how nAChRs containing these subunits may regulate NTS neurochemical systems such as GLP-1. To achieve this goal we propose to use an innovative mouse nicotine IVSA technique to test the effect of specific gene knockouts on volitional nicotine intake. In addition, we plan to employ cutting-edge viral- mediated gene transfer technologies to re-express or silence target genes in vivo, as well as immunochemical techniques for brain region-specific assessment of neuronal activation, and intracranial self-stimulation for direct inquiry of reward systems in rats and mice. Results from the experiments outlined in this proposal will increase our basic understanding of nicotine addiction, and may provide exciting targets for the development of novel therapeutics for smoking cessation. PUBLIC HEALTH RELEVANCE: Neurobiological mechanisms of nicotine reinforcement: Role of the nucleus tractus solitarius (NTS) Estimates project that by the year 2020, tobacco-related disease will become the largest single health problem world-wide, resulting in approximately 8.4 million deaths annually [12]. This research proposal seeks to provide a better understanding of the fundamental neurobiology underlying nicotine addiction. Results from these experiments may serve to develop novel therapeutics for smoking cessation.

描述（由适用提供）：尼古丁增强的神经生物学机制：核纳克斯·斯托里斯（NTS）吸烟的作用是发达国家可预防死亡和疾病的主要原因，每年在美国每年花费大约1600亿美元，以支付导致疾病的直接医疗保健费用。尼古丁是负责烟草成瘾的烟草烟雾的主要精神活性组成部分。尼古丁通过刺激烟碱乙酰胆碱受体（NACHRS）来起作用，这些乙酰胆碱受体（NACHR）是由五个离散亚基组成的五聚离子通道。我们对吸烟行为的理解的主要进步是，最近发现，染色体区域15q25上A3/ A5/€4 NACHR亚基基因簇的遗传变异显着增加了烟草成瘾的风险。有趣的是，A3/ A5/»4 NACHR亚基在大脑中具有高度限制的表达模式，而固体道（NTS）的核us是显示所有三个亚基的唯一稳健表达的大脑区域之一。 NTS参与了喂养，呼吸，互感信息处理的调节，并最近实施了优化奖励，但其在尼古丁增强中的作用仍然很大程度上出乎意料。初步数据表明，利多卡因介导的NT灭活可显着降低大鼠静脉内尼古丁自我给药（IVSA）。此外，在NTS中产生了胰高血糖素样肽-1（GLP-1），一种参与调节互感互压和进食抑制的神经肽，代表了其主要有效系统之一，投影了与药物增强相关的大脑区域。初步数据表明，NTS中的GLP-1神经元因急性尼古丁注射而被激活。此外，初步研究表明，缺乏GLP-1受体表达的小鼠几乎完全废除了尼古丁IVSA。综上所述，这些结果表明NTS和GLP-1传播在尼古丁增强中具有调节作用。我们的目的是表征A3/ A5和/或4个含NACHR在NTS中的NACHR的作用，以及NACHR含有这些亚基的NACHR如何调节NTS神经化学系统，例如GLP -1。为了实现这一目标，我们建议使用创新的小鼠尼古丁IVSA技术来测试特定基因敲除对自愿尼古丁摄入的影响。此外，我们计划采用尖端的病毒介导的基因转移技术来重新表达或沉默的靶基因体内，以及免疫化学技术，用于对神经元激活的大脑区域特异性评估，以及颅内自我刺激，以直接询问大鼠和小鼠的奖励系统。该提案中概述的实验的结果将增加我们对尼古丁添加的基本理解，并可能为开发新型戒烟治疗提供令人兴奋的目标。 公共卫生相关性：尼古丁增强的神经生物学机制：核心核团结核（NTS）的作用估计，到2020年，与烟草相关的疾病将成为全球最大的单一健康问题，每年大约840万人死亡[12]。该研究建议旨在更好地了解尼古丁成瘾的基本神经生物学。这些实验的结果可能有助于开发新的戒烟疗法。