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: 10231269
• 负责人: Cassandra D Gipson-Reichardt
• 金额: $ 36.83万
• 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/10231269
• 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.

项目摘要/摘要 尼古丁滥用和成瘾是公共卫生的重大负担。尼古丁，一种活性生物碱，在 烟草，是对雪茄、香烟和汽化等含烟草产品上瘾的原因 液体电子烟。鉴于尼古丁成瘾对健康的巨大负面影响，以及最近尼古丁成瘾的激增 随着含尼古丁电子烟的普及，对电子烟的创新研究非常必要 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，特别是伏隔核核心(NAcore)。纳科雷 谷氨酸能机制参与尼古丁复发，包括突触的快速、瞬时增强 强度(t-SP；测量为AMPA/NMDA比值增加)和伴随的谷氨酸受体变化。 由于吸烟行为对线索的依赖，接触尼古丁相关线索是复发的危险因素。 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药物，目前在 研究表明，作为一种成瘾疗法，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(GLT-1)。此外，在R00奖励期间收集的初步数据表明，NAcore GLT-1的修复对于NAC减少尼古丁寻求是必要的，并且NAC抑制其前体的表达。 炎症细胞因子，肿瘤坏死因子α(肿瘤坏死因子α)，在NAcore内。肿瘤坏死因子α激活核因子- Kappa B(NF-κB)信号转导和调节学习、记忆和突触可塑性。因此，在目标1中，我们建议 探讨核因子-κB信号在尼古丁自我给药和线索尼古丁寻找中的作用。同样，这也是 AIM将确定在提示尼古丁复发期间肿瘤坏死因子α信号是否影响t-SP，以及单抗是否 针对肿瘤坏死因子，α可以抑制这些异常过程。重要的是，肿瘤坏死因子α单抗被用于临床。 用于治疗自身免疫性疾病，并已知能抑制肿瘤坏死因子α与其受体结合。然后Aim 2将决定 小胶质细胞在t-SP和尼古丁寻找化学遗传学中的作用有趣的是，我们发现GLT-1 在提示的尼古丁寻找过程中，随着t-SP的表达迅速增加。然而，目前还不清楚这是不是 神经炎症调节并伴随星形胶质细胞和小胶质细胞向突触迁移 尼古丁寻求者。因此，在目标3中，我们建议使用化学遗传学来双向控制小胶质细胞 确定他们在寻找尼古丁的过程中控制NAcore星形胶质细胞-突触接触的能力。总而言之，调查结果 这些研究将揭示神经炎性信号在尼古丁自身中的积极、动态作用。 给药和线索驱动的尼古丁复发相关的突触可塑性，并拓宽了我们的 目前对尼古丁成瘾的神经生物学机制的理解。