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

基本信息

  • 批准号:
    8369807
  • 负责人:
  • 金额:
    $ 2.92万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
描述(由申请人提供):尼古丁强化的神经生物学机制:孤立束核(NTS)的作用在发达国家,吸烟是可预防的死亡和疾病的主要原因,在美国,每年大约花费1600亿美元用于支付由此引起的疾病的直接医疗费用。尼古丁是烟草烟雾中导致烟草成瘾的主要精神活性成分。尼古丁通过刺激尼古丁乙酰胆碱受体(nachr)在大脑中起作用,nachr是由五个离散亚基组成的五聚体离子通道。我们对吸烟行为的理解取得了重大进展,最近发现染色体15q25区域a3/ a5/¿4 nAChR亚基基因簇的遗传变异显著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受限的表达模式,孤立束核(NTS)是唯一显示所有三个亚基都强烈表达的大脑区域之一。NTS参与摄食、呼吸、内感受信息处理的调节,最近还被认为与阿片类奖赏有关,但其在尼古丁强化中的作用仍未得到充分研究。初步数据显示,利多卡因介导的NTS失活可显著降低大鼠静脉尼古丁自我给药(IVSA)。此外,胰高血糖素样肽-1 (GLP-1),一种参与调节内感受性应激和摄食抑制的神经肽,在NTS中产生,代表其主要的传出系统之一,投射到与药物强化相关的大脑区域。初步数据显示,NTS中的GLP-1神经元在急性尼古丁注射后被激活。此外,初步研究表明,在GLP-1受体缺乏表达的小鼠中,尼古丁IVSA几乎完全被消除。综上所述,这些结果表明NTS和GLP-1的传递在尼古丁强化中起着调节作用。我们的目标是表征含有a3/ a5和/或含有¿4的nAChRs在尼古丁强化NTS中的作用,以及含有这些亚基的nAChRs如何调节NTS神经化学系统,如GLP-1。为了实现这一目标,我们建议使用一种创新的小鼠尼古丁IVSA技术来测试特定基因敲除对自愿尼古丁摄入量的影响。此外,我们计划采用尖端的病毒介导的基因转移技术在体内重新表达或沉默靶基因,以及免疫化学技术用于大脑区域特异性评估神经元激活,以及颅内自我刺激用于直接询问大鼠和小鼠的奖励系统。本提案中概述的实验结果将增加我们对尼古丁成瘾的基本了解,并可能为戒烟新疗法的发展提供令人兴奋的目标。

项目成果

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Luis Miguel Tuesta其他文献

Luis Miguel Tuesta的其他文献

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{{ truncateString('Luis Miguel Tuesta', 18)}}的其他基金

Microglia and Epigenetic Regulation in Opioid Addiction
阿片类药物成瘾中的小胶质细胞和表观遗传调控
  • 批准号:
    10201552
  • 财政年份:
    2020
  • 资助金额:
    $ 2.92万
  • 项目类别:
Microglia and Epigenetic Regulation in Opioid Addiction
阿片类药物成瘾中的小胶质细胞和表观遗传调控
  • 批准号:
    10621775
  • 财政年份:
    2020
  • 资助金额:
    $ 2.92万
  • 项目类别:
Microglia and Epigenetic Regulation in Opioid Addiction
阿片类药物成瘾中的小胶质细胞和表观遗传调控
  • 批准号:
    10409766
  • 财政年份:
    2020
  • 资助金额:
    $ 2.92万
  • 项目类别:
Role of Dopamine Neuron-Specific Gene Enhancers in Cocaine Relapse
多巴胺神经元特异性基因增强剂在可卡因复发中的作用
  • 批准号:
    10452555
  • 财政年份:
    2019
  • 资助金额:
    $ 2.92万
  • 项目类别:
Role of Dopamine Neuron-Specific Gene Enhancers in Cocaine Relapse
多巴胺神经元特异性基因增强剂在可卡因复发中的作用
  • 批准号:
    10207578
  • 财政年份:
    2019
  • 资助金额:
    $ 2.92万
  • 项目类别:
Role of Dopamine Neuron-Specific Gene Enhancers in Cocaine Relapse
多巴胺神经元特异性基因增强剂在可卡因复发中的作用
  • 批准号:
    10157603
  • 财政年份:
    2019
  • 资助金额:
    $ 2.92万
  • 项目类别:
Role of Dopamine Neuron-Specific Gene Enhancers in Cocaine Relapse
多巴胺神经元特异性基因增强剂在可卡因复发中的作用
  • 批准号:
    9980860
  • 财政年份:
    2019
  • 资助金额:
    $ 2.92万
  • 项目类别:
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
  • 财政年份:
    2011
  • 资助金额:
    $ 2.92万
  • 项目类别:

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  • 批准号:
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