The Role of Microbiome Composition in Amphetamine Abuse

微生物组组成在安非他明滥用中的作用

基本信息

批准号：
10656799
负责人：
Angela Michelle Carter
金额：
$ 54.22万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656799
关键词：
Acetates Acetylation Adult Affect Amino Acids Amphetamine Abuse Amphetamines Animal Model Attention Deficit Disorder Attention deficit hyperactivity disorder Behavior Brain Butyrates Cessation of life Chemosensitization Communication Courtship Cytoplasm Data Disease Dopamine Drosophila genus Drosophila melanogaster Exposure to Family member Fermentation Fusobacterium nucleatum Geography Germ-Free Gingivitis Gnotobiotic Grooming Growth HDAC1 gene Health Histone Deacetylase Inhibitor Human Laboratories Lead Locomotion Mediating Messenger RNA Mississippi Modeling Molecular Motor Activity Neuroglia Neurons Oral Administration Outcome Pathogenesis Periodontitis Persons Pharmaceutical Preparations Play Process Property Proteins Publishing RNA Interference Reporting Rodent Role Stimulant Substance Use Disorder Techniques Testing Time Translating United States Substance Abuse and Mental Health Services Administration Volatile Fatty Acids Western Blotting abuse liability amphetamine use behavioral phenotyping behavioral response blood-brain barrier crossing chromatin immunoprecipitation court dopamine transporter drug of abuse dysbiosis experience experimental study extracellular fly genetic manipulation gut colonization gut microbiome gut microbiota gut-brain axis histone acetyltransferase in vivo inhibitor microbial products microbiome microbiome composition neuropsychiatric disorder pharmacologic preference promoter psychostimulant stimulant abuse

项目摘要

Project Summary/Abstract: Amphetamines (AMPHs) are psychostimulants commonly used for the treatment of neuropsychiatric disorders (e.g. attention deficit disorders). They are also abused, with devastating outcomes. The abuse potential of AMPHs is associated with their ability to cause mobilization of cytoplasmic dopamine (DA), which leads to an increase in extracellular DA levels. This increase is mediated by the reversal of the DA transporter (DAT) function, which causes non-vesicular DA release, here defined as DA efflux. Notably, inhibition of DA efflux reduces both the ability of AMPH to increase motor activity and AMPH preference8-10. Imbalances in the gut microbiome (dysbiosis) have been suggested to participate in the pathogenesis of substance use disorders11. In addition, psychostimulant abuse promotes dysbiosis12-15. Therefore, it is possible that changes in the gut microbiome and its metabolites may not only be a consequence of substance use disorders, but may play a role in mediating the behavioral responses to drugs of abuse11. Microbial products, such as short-chain fatty acids (SCFAs), are thought to play a fundamental role in regulating the gut-brain axis16. Among SCFAs, butyrate is known to cross the BBB and directly act on neurons and glial cells17. Fusobacterium nucleatum (F. nucleatum) is an anaerobic, filamentous, gram-negative bacterial species that secretes butyrate18, the growth of which is stimulated by AMPH abuse13-15. Our data demonstrate that in germ-free (gnotobiotic) Drosophila, colonization with F. nucleatum enhances AMPH-induced DA effluxes (recorded in isolated fly brains), as well as AMPH behaviors. This potentiation of AMPH actions by F. nucleatum is paralleled by oral administration of butyrate. To understand, mechanistically, how F. nucleatum promotes AMPH actions, it is important to consider that changes in DAT expression regulate both AMPH-induced DA efflux and psychomotor actions19. Also, butyrate is a potent inhibitor of histone deacetylases (HDACs)20-22; inhibition of HDACs robustly increases expression of both DAT mRNA and proteins21-23. Our hypothesis is that F. nucleatum enhances AMPH actions by elevating DAT expression. This is mediated by secretion of butyrate, HDAC inhibition, and enhanced Drosophila DAT (dDAT) promotor acetylation. We will test this hypothesis through the following specific aims: S.A. #1. To determine how F. nucleatum regulates dDAT expression. S.A. #2. To test, mechanistically, how F. nucleatum increases AMPH-induced DA efflux. The experiments of S.A. #1-2 will be performed in isolated Drosophila brains, a model our laboratory developed to study AMPH actions ex vivo. Furthermore, using adult Drosophila, we will be able to translate the molecular discoveries of S.A. #1-2 to specific AMPH behavioral phenotypes. Thus, S.A. #3 focuses on behavior. S.A. #3. To define how F. nucleatum enhances AMPH behaviors.

项目摘要/摘要：安非他明 (AMPH) 是常用于治疗的精神兴奋剂神经精神疾病（例如注意力缺陷障碍）。他们还受到虐待，造成毁灭性的后果。 AMPH 的滥用潜力与其引起细胞质多巴胺动员的能力有关 (DA)，导致细胞外 DA 水平增加。这种增加是由 DA 的逆转介导的转运蛋白 (DAT) 功能，导致非囊泡 DA 释放，此处定义为 DA 流出。尤其，抑制 DA 外流会降低 AMPH 增加运动活动的能力和 AMPH 偏好8-10。肠道微生物组失衡（生态失调）被认为参与了以下疾病的发病机制：物质使用障碍11。此外，滥用精神兴奋剂会导致生态失调12-15。因此，有可能肠道微生物组及其代谢物的变化可能不仅仅是物质使用的结果失调，但可能在调节对滥用药物的行为反应中发挥作用11。微生物产品，例如短链脂肪酸 (SCFA)，被认为在调节肠脑轴16。在短链脂肪酸中，丁酸盐已知可以穿过血脑屏障并直接作用于神经元和神经胶质细胞17。具核梭杆菌 (F. nucleatum) 是一种厌氧、丝状、革兰氏阴性细菌分泌丁酸的物种18，其生长受到 AMPH 滥用的刺激13-15。我们的数据表明，在无菌（无菌）果蝇中，具核梭菌的定植增强了 AMPH 诱导的 DA 流出（在离体果蝇大脑中记录）以及 AMPH 行为。这种增强作用 F. nucleatum 的 AMPH 作用与口服丁酸盐并行。机械地理解， F. nucleatum 如何促进 AMPH 作用，重要的是要考虑 DAT 表达的变化调节 AMPH 诱导的 DA 外流和精神运动行为19。此外，丁酸盐是组蛋白的有效抑制剂脱乙酰酶 (HDAC)20-22；抑制 HDAC 会显着增加 DAT mRNA 和蛋白质21-23。我们的假设是具核梭杆菌通过提高 DAT 表达来增强 AMPH 作用。这是调解的通过丁酸分泌、HDAC 抑制和增强果蝇 DAT (dDAT) 启动子乙酰化。我们将通过以下具体目标检验这一假设： SA#1。确定具核梭菌如何调节 dDAT 表达。 SA#2。从机制上测试 F. nucleatum 如何增加 AMPH 诱导的 DA 流出。 S.A. #1-2 的实验将在离体果蝇大脑中进行，这是我们实验室开发的模型研究 AMPH 离体作用。此外，利用成年果蝇，我们将能够翻译分子 S.A. #1-2 对特定 AMPH 行为表型的发现。因此，S.A.#3 关注的是行为。 SA#3。定义具核梭菌如何增强 AMPH 行为。