Neuroinflammatory and glutamatergic mechanisms of nicotine seeking

寻求尼古丁的神经炎症和谷氨酸机制

• 批准号: 10214266
• 负责人: Cassandra D Gipson-Reichardt
• 金额: $ 38.27万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214266
• 关键词: Abstinence; Acetylcysteine; Alkaloids; Anti-Inflammatory Agents; Antioxidants; Astrocytes; Attenuated; Autoimmune Diseases; Award; Binding; Blood - brain barrier anatomy; Brain; Brain region; Cells; Chemosensitization; Chronic; Cigar; Cigarette; Clinical; Cocaine; Complex; Cues; Data; Development; Electronic cigarette; Electrophysiology (science); FDA approved; Gene Transfer; Glean; Glutamate Receptor; Glutamate Transporter; Glutamates; Health; Immunohistochemistry; Individual; Inflammatory; Intervention; Investigation; Knowledge; Label; Learning; Measures; Mediating; Membrane; Memory; Microglia; Monoclonal Antibodies; Morphology; N-Methylaspartate; NF-kappa B; Neurobiology; Neurons; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nucleus Accumbens; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phosphotransferases; Pre-Clinical Model; Process; Public Health; Relapse; Research; Rewards; Rheumatoid Arthritis; Risk Factors; Role; Self Administration; Signal Transduction; Smoker; Smoking; Smoking Behavior; Structure; Synapses; Synaptic plasticity; TNF gene; Techniques; Testing; Therapeutic; Time; Tobacco; Tobacco use; Viral; Visualization; Western Blotting; Withdrawal; addiction; base; cell motility; craving; cytokine; designer receptors exclusively activated by designer drugs; drug abstinence; drug reward; electronic liquid; glutamatergic signaling; innovation; insight; migration; neurobiological mechanism; neuroinflammation; nicotine abuse; nicotine exposure; nicotine seeking behavior; nicotine use; novel; novel strategies; novel therapeutics; prevent; receptor; response; restoration; selective expression; small molecule; smoking abstinence; smoking addiction; tool; vaping; vapor

PROJECT SUMMARY/ABSTRACT Nicotine abuse and addiction represent a significant burden to public health. Nicotine, an active alkaloid in tobacco, is responsible for addiction to tobacco-containing products such as cigars, cigarettes, and vaporized liquid e-cigarettes. Given the immense negative health impact of nicotine addiction as well as the recent surge in popularity of nicotine-containing e-cigarettes, there is a great need for innovative research on the neurobiological underpinnings of nicotine addiction and relapse. Nicotine produces cellular adaptations in brain regions associated with drug reward, especially within the nucleus accumbens core (NAcore). NAcore glutamatergic mechanisms are involved in nicotine relapse, including rapid, transient potentiation of synaptic strength (t-SP; measured as increased AMPA to NMDA ratios) and accompanying glutamate receptor changes. Due to the cue dependency of smoking behavior, exposure to nicotine-associated cues is a risk factor for relapse. We and others recently found that N-acetylcysteine (NAC), an antioxidant and anti-inflammatory currently under investigation as an addiction therapeutic, appears to inhibit nicotine cue-associated t-SP and restore glial glutamate transport (GLT-1). As well, preliminary data collected during an R00 award period indicate that NAcore GLT-1 restoration is necessary for NAC to reduce nicotine seeking, and NAC inhibits expression of the pro- inflammatory cytokine, tumor necrosis factor alpha (TNFα), within the NAcore. TNFα activates nuclear factor- kappa B (NF-κB) signaling and regulates learning, memory, and synaptic plasticity. Thus, in Aim 1 we propose to characterize the role of NF-κB signaling in nicotine self-administration and cued nicotine seeking. As well, this aim will determine if TNFα signaling impacts t-SP during cued nicotine relapse, and if a monoclonal antibody against TNFα can inhibit these aberrant processes. Importantly, TNFα monoclonal antibodies are used clinically for autoimmune disorders and are known to inhibit TNFα from binding to its receptor. Aim 2 will then determine the role of microglia in t-SP and nicotine seeking using chemogenetics. Interestingly, we have found that GLT-1 expression rapidly increases along with t-SP during cued nicotine seeking. It is unclear, however, if this is regulated by neuroinflammation and accompanied by astrocyte and microglial migration to the synapse during nicotine seeking. Therefore, in Aim 3 we propose to bi-directionally control microglia using chemogenetics to determine their ability to gate NAcore astrocyte-synaptic contact during nicotine seeking. In conclusion, findings from these investigations will uncover an active, dynamic role of neuroinflammatory signaling in nicotine self- administration and cue-driven nicotine relapse-associated synaptic plasticity, and broaden the scope of our current understanding of neurobiological mechanisms underlying nicotine addiction.

项目总结/摘要 尼古丁滥用和成瘾是公共卫生的重大负担。尼古丁是一种活性生物碱， 烟草，是负责上瘾的含烟草产品，如雪茄，香烟，和蒸发 液体电子烟鉴于尼古丁成瘾对健康的巨大负面影响以及最近的激增， 随着含尼古丁电子烟的普及，非常需要对尼古丁的含量进行创新研究。 尼古丁成瘾和复发的神经生物学基础。尼古丁在大脑中产生细胞适应 与药物奖赏相关的区域，特别是在核神经元核心（NAcore）内。NAcore 尼古丁复吸涉及神经递质能机制，包括快速、短暂的突触增强， 强度（t-SP;测量为AMPA与NMDA比率增加）和伴随的谷氨酸受体变化。 由于吸烟行为的线索依赖性，暴露于尼古丁相关的线索是复发的风险因素。 我们和其他人最近发现，N-乙酰半胱氨酸（NAC），一种抗氧化剂和抗炎剂， 研究表明，作为一种成瘾治疗剂，似乎可以抑制尼古丁线索相关的t-SP，并恢复神经胶质细胞 谷氨酸转运蛋白（GLT-1）。此外，在R 00授予期间收集的初步数据表明，NAcore GLT-1的恢复是NAC减少尼古丁寻求所必需的，NAC抑制了GLT-1前体的表达。 炎性细胞因子，肿瘤坏死因子α（TNFα），在NAcore内。TNFα激活核因子- κ B（NF-κB）信号传导并调节学习、记忆和突触可塑性。因此，在目标1中，我们提出 研究NF-κB信号在尼古丁自我给药和尼古丁寻求线索中的作用。同样， 目的是确定在提示尼古丁复吸期间TNFα信号传导是否影响t-SP，以及单克隆抗体 抗TNFα可以抑制这些异常过程。重要的是，TNFα单克隆抗体用于临床 用于自身免疫性疾病，已知可抑制TNFα与其受体结合。目标2将确定 利用化学遗传学研究小胶质细胞在t-SP和尼古丁寻求中的作用。有趣的是，我们发现GLT-1 在线索尼古丁寻求过程中，表达沿着t-SP迅速增加。然而，目前尚不清楚这是否 由神经炎症调节，并伴有星形胶质细胞和小胶质细胞迁移到突触， 寻找尼古丁因此，在目标3中，我们提出使用化学遗传学双向控制小胶质细胞， 确定它们在尼古丁寻求过程中门控NAcore星形胶质细胞-突触接触的能力。总之，调查结果 从这些调查将揭示一个积极的，动态的作用，神经炎症信号在尼古丁自我， 管理和线索驱动的尼古丁复发相关的突触可塑性，并扩大我们的范围， 目前对尼古丁成瘾的神经生物学机制的理解。