Advisory Committee Chair
Karen L Gamble
Advisory Committee Members
Jeremy J Day
Jennifer J Derberry
Aurelio Galli
Craig M Powell
Lucas D Pozzo-Miller
Document Type
Dissertation
Date of Award
2023
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Amphetamine (AMPH), a psychostimulant commonly prescribed for the treatment of neuropsychiatric and neurological disorders, has a high liability for abuse. The stimulant properties of AMPH are primarily associated with its ability to increase dopamine (DA) neurotransmission. This increase is mediated by non-vesicular DA release (DA efflux). This DA efflux is the result of the reversal of the DA transporter (DAT), which is promoted by AMPH. Syntaxin 1 (Stx1), a SNARE protein, interacts with the DAT N-terminus. Stx1 is phosphorylated at Ser14 by casein kinase II (CK2). This phosphorylation site contributes to the DAT/Stx1 interaction and is critical for allowing DAT to enter an efflux willing conformation. Additionally, we examined the role of the gut microbiome in AMPH response. AMPH consumption leads to changes in the gut microbiome of both humans and rodents. Notably, Fusobacteria nucleatum (F. nucleatum) is a bacterium that increases in abundance in response to AMPH. This bacterium produces the short chain fatty acid (SCFA) butyrate, an HDAC inhibitor. Using Drosophila as an animal model, we address the behavioral significance of reverse transport of DA in the context of both Stx1 phosphorylation as well as microbiome composition. Preventing Stx1 phosphorylation in Drosophila significantly reduces DA efflux and AMPH-associated behaviors. Furthermore, colonizing the Drosophila gut with F. nucleatum increased DAT expression and enhanced behavioral response to AMPH, via the release of the SCFA butyrate. Our results suggest that there are multiple potential targets for the treatment of AMPH abuse. First, pharmacologically targeting Stx1 phosphorylation by inhibiting CK2 is a feasible strategy as it blocked the reverse transport of DA and inhibited AMPH preference in our animal model. Second, the microbiome is an intriguing alternative target for treatment of AMPH abuse. While a deeper mechanistic understanding of the interplay between AMPH and the microbiome is needed, our data demonstrate the existence of an individual bacterium that drives AMPH response. It is possible that reshaping of an individual’s gut microbiome via both probiotics and antibiotics could be a feasible treatment for AMPH abuse.
Recommended Citation
Mabry, Samuel James, "Molecular Mechanisms of Amphetamine Abuse" (2023). All ETDs from UAB. 28.
https://digitalcommons.library.uab.edu/etd-collection/28