Neuroinflammatory and glutamatergic mechanisms of nicotine seeking

寻求尼古丁的神经炎症和谷氨酸机制

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要尼古丁滥用和成瘾对公众健康造成了重大负担。尼古丁是一种活性生物碱。烟草，是导致对雪茄、香烟和汽化烟草等含烟草产品成瘾的原因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，非常需要对其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，尤其是伏隔核核心（NAcore）内。谷氨酸能机制参与尼古丁复吸，包括突触的快速、短暂增强强度（t-SP；以 AMPA 与 NMDA 比率增加来衡量）和伴随的谷氨酸受体变化。由于吸烟行为的线索依赖性，接触尼古丁相关线索是复吸的危险因素。我们和其他人最近发现N-乙酰半胱氨酸（NAC），一种目前正在研究的抗氧化剂和抗炎剂作为一种成瘾治疗方法进行研究，似乎可以抑制尼古丁提示相关的 t-SP 并恢复神经胶质细胞谷氨酸转运 (GLT-1) 此外，在 R00 授予期间收集的初步数据表明 NAcore。 GLT-1 恢复对于 NAC 减少尼古丁寻求是必要的，并且 NAC 抑制前体的表达 NAcore 内的炎症细胞因子、肿瘤坏死因子 α (TNFα) 会激活核因子。 kappa 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。表征 NF-κB 信号在尼古丁自我给药和提示尼古丁寻找中的作用。目标将确定 TNFα 信号传导是否会在提示尼古丁复发期间影响 t-SP，以及单克隆抗体是否会影响 t-SP 抗 TNFα 可以抑制这些异常过程，重要的是，TNFα 单克隆抗体已用于临床。用于自身免疫性疾病，并已知可抑制 TNFα 与其受体的结合，然后将确定目标 2。利用化学遗传学研究小胶质细胞在 t-SP 和尼古丁中的作用，我们发现了 GLT-1。在提示尼古丁寻找过程中，表达随着 t-SP 迅速增加，然而，尚不清楚这是否是这样。受神经炎症调节，并伴随着星形胶质细胞和小胶质细胞向突触的迁移因此，在目标 3 中，我们建议使用化学遗传学双向控制小胶质细胞。确定它们在寻找尼古丁期间控制 NAcore 星形胶质细胞-突触接触的能力。这些研究将揭示神经炎症信号在尼古丁自我调节中的积极、动态的作用管理和提示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神经生物学机制的了解。