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：苯丙胺（AMPHS）是通常用于治疗的精神刺激药神经精神疾病（例如，注意力缺陷障碍）。他们也受到虐待，结果造成了毁灭性的结果。 AMPHS的滥用潜力与它们引起细胞质多巴胺动员的能力有关（DA），导致细胞外DA水平的增加。这种增加是由DA的逆转介导的转运蛋白（DAT）函数，导致非Xicular DA释放，此处定义为DA外排。尤其， DA外排的抑制既降低了AMPH增加运动活性的能力，又降低了AMPH首选项8-10。肠道微生物组（营养不良）的失衡已被建议参与物质使用障碍11。此外，精神刺激滥用会促进营养不良12-15。因此，有可能肠道微生物组及其代谢产物的变化不仅可能是使用物质的结果疾病，但可能在调解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），被认为在调节肠道轴16。在SCFA中，已知丁酸可以穿越BBB并直接对神经元起作用和神经胶质细胞17。核细菌核（F. nucleatum）是一种厌氧，丝状，革兰氏阴性细菌分泌丁酸酯的物种18，其生长受到Amph滥用的刺激13-15。我们的数据表明，在无菌（gnotobiotic）果蝇中，核链球菌定植会增强 AMPH诱导的DA外排（以孤立的苍蝇大脑记录）以及AMPH行为。这种增强 F. nucleatum的AMPH作用与口服丁酸酯相似。理解机械理解 F. nutleatum如何促进AMPH的作用，重要的是要考虑DAT表达的变化调节 Amph诱导的DA外排和精神运动动作19。另外，丁酸是组蛋白的有效抑制剂脱乙酰基酶（HDACS）20-22; HDAC的抑制作用可稳健地增加DAT mRNA和蛋白质21-23。我们的假设是F. nutleatum通过升高DAT表达来增强AMPH的作用。这是介导的通过分泌丁酸酯，HDAC抑制和增强果蝇DAT（DDAT）启动子乙酰化。我们将通过以下特定目的检验该假设： S.A.＃1。确定F.核如何调节DDAT表达。 S.A.＃2。从机械上测试，F。nubleatum如何增加Amph诱导的DA外排。 S.A.＃1-2的实验将在孤立的果蝇大脑中进行，这是我们开发的模型研究Amph的动作。此外，使用成年果蝇，我们将能够翻译分子 S.A.＃1-2的发现对特定的AMPH行为表型。因此，S.A.＃3专注于行为。 S.A.＃3。定义F. nutleatum如何增强AMPH行为。