<i>Fusobacterium nucleatum</i> enhances amphetamine-induced behavioral responses through a butyrate-driven epigenetic mechanism

Amphetamines are psychostimulants that are commonly used to treat neuropsychiatric disorders and are prone to misuse. The pathogenesis of amphetamine use disorder (AUD) is associated with dysbiosis (an imbalance in the body's microbiome) and bacterially produced short-chain fatty acids (SCFAs), which are implicated in the gut-brain axis. Amphetamine exposure in both rats and humans increases the amount of intestinal <i>Fusobacterium nucleatum</i>, which releases SFCAs. Here, we found that colonization of gnotobiotic <i>Drosophila melanogaster</i> with <i>F. nucleatum</i> or supplementing the flies' diet with the SCFA butyrate enhanced the psychomotor and reward properties of amphetamine. Butyrate inhibits histone deacetylases (HDACs), and knockdown of HDAC1 recapitulated the effects induced by <i>F. nucleatum</i> or butyrate. The enhancement in amphetamine-induced behaviors was mediated by an increase in the amount of released dopamine that resulted from amphetamine-induced reversal of dopamine transporter (DAT) function, termed nonvesicular dopamine release (NVDR). The magnitude of amphetamine-induced NVDR was partially mediated by an increase in DAT abundance stimulated at a transcriptional level, and the administration of <i>F. nucleatum</i> or butyrate enhanced NVDR by increasing DAT expression. The findings indicate that <i>F. nucleatum</i> supports AUD through epigenetic regulation of dopamine signaling and identify potential targets for AUD treatment.