Neuroimmunomodulation of nicotine relapse and synaptic plasticity

尼古丁复吸和突触可塑性的神经免疫调节

• 批准号: 9761009
• 负责人: Mark D Namba
• 金额: $ 4.42万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761009
• 关键词: Abstinence; Accounting; Acetylcysteine; Adult; Attention; Attenuated; Bupropion; Caliber; Cessation of life; Chantix; Chemosensitization; Chronic; Cocaine; Confocal Microscopy; Cues; Dendritic Spines; Development; Dimensions; Drug usage; Extinction (Psychology); Extracellular Matrix; Future; Gelatinase B; Gene Transfer; Glutamate Transporter; Glutamates; Goals; Head; Health; Immunohistochemistry; Individual; Knowledge; Learning; Matrix Metalloproteinases; Measures; Mediating; Memory; Mental Depression; Molecular; Monoclonal Antibodies; Mood Disorders; Morphology; NF-kappa B; Neurobiology; Neurodegenerative Disorders; Neuroimmunomodulation; Neurons; Nicotine; Nicotine Dependence; Nucleus Accumbens; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phosphotransferases; Play; Process; Public Health; Rattus; Relapse; Replacement Therapy; Research; Rewards; Rodent; Rodent Model; Role; Self Administration; Series; Shapes; Signal Pathway; Signal Transduction; Smoking Cessation Intervention; Stimulus; Structure; Synapses; Synaptic plasticity; TNF gene; Techniques; Therapeutic Effect; Three-dimensional analysis; Time; Tobacco use; Training; United States; Viral; Viral Vector; Withdrawal; addiction; biological adaptation to stress; cellular imaging; classical conditioning; clinical efficacy; cytokine; design; drug of abuse; drug relapse; drug seeking behavior; effective therapy; experimental study; frontier; functional plasticity; genetic manipulation; glutamatergic signaling; neuroadaptation; neurobehavioral; neurobiological mechanism; neuroinflammation; neuropsychiatric disorder; nicotine cessation; nicotine exposure; nicotine replacement; nicotine seeking behavior; novel; postsynaptic; preventable death; reconstruction; response; restoration; smoking abstinence; smoking cessation; tobacco abstinence; tobacco abuse; treatment strategy; tumor necrosis factor-alpha inhibitor; varenicline

Project Summary/Abstract Tobacco abuse is a significant health concern and remains the leading cause of preventable death in the United States, accounting for nearly one in five deaths in US adults. Smoking cessation treatment strategies, such as nicotine replacement therapy or varenicline (Chantix®), have shown some clinical efficacy in helping individuals quit smoking. However, high rates of relapse persist even for individuals receiving replacement therapy, which highlights the need for a more holistic understanding of the neurobiological underpinnings of nicotine addiction and relapse to better promote long-term abstinence from tobacco use. Maladaptive glutamatergic plasticity has been implicated across several major drugs of abuse and these synaptic alterations mediate the associative learning processes that occur between environmental stimuli and drugs of abuse. Specifically, cue-induced reinstatement of nicotine seeking in rats is associated with rapid, transient synaptic potentiation (t-SP) of medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore), as measured by an increase in dendritic spine head diameter (dh) as well as activation of extracellular matrix metalloproteinases (MMPs). The underlying molecular and cellular mechanisms that modulate this structural and functional plasticity remains poorly understood. Particularly, it is not known if neuroinflammatory mechanisms modulate the expression of these synaptic alterations. Thus, I propose to examine the role of proinflammatory tumor necrosis factor alpha (TNFα) and NF-κB signaling on t-SP in the NAcore using a rodent model of cue-induced nicotine reinstatement. Specifically, I hypothesize that viral-vector mediated inhibition of IκB kinase (IKK, which activates NF-κB) signaling will attenuate t-SP in the NAcore and cue-induced nicotine reinstatement, whereas activation of IKK will potentiate these measures. Additionally, I propose that TNFα signaling underlies postsynaptic t-SP, MMP activation, and cue-induced reinstatement of nicotine seeking. This research has the potential to identify a novel mechanism through which postsynaptic t-SP is produced in response to drug-associated stimuli. As well, this research may reveal a novel and dynamic role for neuroinflammatory mechanisms in drug relapse and may guide the future development of new and effective pharmacotherapeutics. Throughout the duration of the proposed studies, I will be trained in confocal microscopy, three-dimensional analysis of dendritic spine morphology, immunohistochemistry, and viral-vector mediated genetic manipulation.

项目摘要/摘要 烟草滥用是一个重大的健康问题，仍然是统一死亡的主要原因 国家，在美国成年人中占几乎五分之一的死亡。戒烟策略，例如 尼古丁替代疗法或varinicline（Chantix®）在帮助个人方面表现出一些临床效率 戒烟。但是，即使对于接受替代疗法的个人来说，高救济率仍然存在，这 强调需要对尼古丁成瘾的神经生物学基础有更全面的理解 并继电器更好地促进烟草使用的长期禁欲。适应不良的谷氨酸能可塑性具有 在几种主要的滥用药物中暗示了这些合成改变，可以调解关联 环境刺激与滥用药物之间发生的学习过程。具体而言，提示引起 在大鼠中恢复尼古丁寻求尼古丁与培养基快速，短暂突触势（T-SP）有关 伏隔核（Nacore）中的棘神经元（MSN），通过树突状脊柱的增加来测量 头直径（DH）以及细胞外基质金属蛋白酶（MMP）的激活。基础 调节该结构和功能可塑性的分子和细胞机制保持较差 理解。特别是，尚不清楚神经炎症机制是否在调节这些表达 突触改变。我建议研究促炎性肿瘤坏死因子α（TNFα）的作用 使用提示诱导的尼古丁恢复原状的啮齿动物模型，在Nacore中对T-SP的NF-κB信号传导。 具体而言，我假设病毒载体介导的IκB激酶（IKK，激活NF-κB）的抑制作用 信号传导将减弱Nacore和提示诱导的尼古丁恢复原状的T-SP，而IKK的激活 将潜在这些措施。此外，我建议TNFα信号传导是突触后T-SP，MMP的基础 激活以及提示引起的尼古丁寻求恢复。这项研究有可能识别出小说 响应与药物相关刺激产生突触后T-SP的机制。也是如此 研究可能揭示了药物缓解中神经炎症机制的新颖而动态的作用，可能 指导新的有效药物治疗剂的未来开发。在整个过程中 拟议的研究，我将接受共聚焦显微镜，树突状脊柱的三维分析培训 形态学，免疫组织化学和病毒载体介导的遗传操作。