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.

项目概要/摘要 烟草滥用是一个重大的健康问题，并且仍然是美国可预防死亡的主要原因 州，占美国成年人死亡人数的近五分之一。戒烟治疗策略，例如 尼古丁替代疗法或伐尼克兰 (Chantix®) 在帮助个人方面已显示出一些临床功效 戒烟。然而，即使对于接受替代疗法的个体来说，复发率仍然很高，这 强调需要更全面地了解尼古丁成瘾的神经生物学基础 和复发，以更好地促进长期戒烟。适应不良的谷氨酸可塑性 与几种主要的药物滥用有关，这些突触改变介导了联想 环境刺激和滥用药物之间发生的学习过程。具体来说，提示诱导 大鼠尼古丁寻求的恢复与介质的快速、瞬时突触增强（t-SP）有关 通过树突棘的增加来测量伏隔核核心 (NAcore) 中的多棘神经元 (MSN) 头部直径 (dh) 以及细胞外基质金属蛋白酶 (MMP) 的激活。底层的 调节这种结构和功能可塑性的分子和细胞机制仍然很差 明白了。特别是，尚不清楚神经炎症机制是否调节这些基因的表达。 突触改变。因此，我建议检查促炎性肿瘤坏死因子 α (TNFα) 的作用 以及 NAcore 中 t-SP 上的 NF-κB 信号传导，使用提示诱导尼古丁恢复的啮齿动物模型。 具体来说，我假设病毒载体介导了 IκB 激酶（IKK，激活 NF-κB）的抑制 信号传导将减弱 NAcore 中的 t-SP 和提示诱导的尼古丁恢复，而 IKK 的激活 将加强这些措施。此外，我认为 TNFα 信号传导是突触后 t-SP、MMP 的基础 激活和提示诱导的尼古丁寻求恢复。这项研究有可能确定一种新颖的 突触后 t-SP 响应药物相关刺激而产生的机制。还有，这个 研究可能揭示神经炎症机制在药物复发中的新颖且动态的作用，并可能 指导新的有效药物治疗的未来发展。在整个期间 拟议的研究，我将接受共焦显微镜、树突棘三维分析的培训 形态学、免疫组织化学和病毒载体介导的遗传操作。