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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（AMPHs）是一种常用的精神兴奋剂