# The Role of Microbiome Composition in Amphetamine Abuse

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $542,166

## Abstract

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.

## Key facts

- **NIH application ID:** 10656799
- **Project number:** 1R01DA056484-01A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Angela Michelle Carter
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $542,166
- **Award type:** 1
- **Project period:** 2023-08-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10656799

## Citation

> US National Institutes of Health, RePORTER application 10656799, The Role of Microbiome Composition in Amphetamine Abuse (1R01DA056484-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10656799. Licensed CC0.

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