Microbial short-chain fatty acids regulate drug seeking and transcriptional control in a model of cocaine seeking

Abstract

Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect. However, the role of the gut microbiome and its metabolites in modulating cocaine-seeking behavior after prolonged abstinence is unknown. Given that relapse prevention is the most clinically challenging issue in treating substance use disorders, studies examining the effects of microbiome manipulations in relapse-relevant models are critical. Here, Sprague-Dawley rats received either untreated water or antibiotics to deplete the gut microbiome and its metabolites. Rats were trained to self-administer cocaine and subjected to either within-session threshold testing to evaluate motivation for cocaine or 21 days of abstinence followed by a cue-induced cocaine-seeking task to model relapse behavior. Microbiome depletion did not affect cocaine acquisition on an FR1 schedule. However, microbiome-depleted subjects exhibited significantly enhanced motivation for low dose cocaine on a within-session threshold task. Similarly, microbiome depletion increased cue-induced cocaine-seeking following prolonged abstinence. In the absence of a normal microbiome, repletion of bacterially-derived SCFA metabolites reversed the behavioral and transcriptional changes associated with microbiome depletion. These findings suggest that gut bacteria, via their metabolites, are key regulators of drug-seeking behaviors, positioning the microbiome as a potential translational research target.

Microbiome Depletion Increases Fentanyl Self-Administration and Alters the Striatal Proteome Through Short-Chain Fatty Acids

“…Similarly, Abx induces reduced CPP for morphine which was reversed with SCFA supplementation ( Hofford et al, 2021b ). More recently, in a model of cocaine self-administration and reinstatement we found that SCFA supplementation reversed the increases in both drug taking and seeking ( Meckel et al, 2023 ). Taken together, these findings place the SCFA as a consistent molecular mechanism that can reverse negative effects of microbiome depletion on behavior.…”

“…One such class that has shown significant mechanistic promise is the short-chain fatty acids (SCFA) which are produced by bacteria when fermenting dietary fiber ( Dalile et al, 2019 ). Oral Abx reduces SCFA in rats to virtually undetectable levels ( Meckel et al, 2023 ). Additionally, previous work from our group has shown that repletion of the three main SCFA in animals with their microbiome depleted by antibiotics restores cocaine and morphine conditioned place preference and cocaine seeking to control levels despite having no measurable effect on the microbiome composition ( Kiraly et al, 2016 ; Hofford et al, 2021b ; Meckel et al, 2023 ).…”

“…Oral Abx reduces SCFA in rats to virtually undetectable levels ( Meckel et al, 2023 ). Additionally, previous work from our group has shown that repletion of the three main SCFA in animals with their microbiome depleted by antibiotics restores cocaine and morphine conditioned place preference and cocaine seeking to control levels despite having no measurable effect on the microbiome composition ( Kiraly et al, 2016 ; Hofford et al, 2021b ; Meckel et al, 2023 ). However, the mechanistic role of SCFA in reversing fentanyl seeking behavior is as yet untested.…”