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

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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, male 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 fixed-ratio 1 schedule. However, microbiome-depleted rats 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 and altered transcriptional regulation in the nucleus accumbens. 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.

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Fig. 1: Abx effects on cocaine taking behaviors.
Fig. 2: Abx increases on cocaine-seeking after abstinence.
Fig. 3: SCFA repletion reverses effects of microbiome depletion on drug-seeking.
Fig. 4: Effects of Abx and SCFA on microbiome composition and function.
Fig. 5: RNA sequencing analysis of NAc after drug seeking.

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Acknowledgements

The authors would like to thank NIDA Drug Supply for provision of cocaine hydrochloride. We would like to thank Alexia Seba-Robles for assistance with animal care. Figures made with BioRender with full permission to publish.

Funding

Funds for this research were provided by NIH grants DA051551 to DDK, DA044308 to DDK, DA050906 to RSH DA053105 to EGP & NS124187 to KRM. As well as a NARSAD Young Investigator award to RSH.

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  1. Twitter: @kiralylab.

Authors and Affiliations

  1. Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Katherine R. Meckel, Arthur Godino, Emily G. Peck, Erin S. Calipari & Drew D. Kiraly

  2. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Katherine R. Meckel, Arthur Godino, Emily G. Peck, Erin S. Calipari, Rebecca S. Hofford & Drew D. Kiraly

  3. Department of Biology, Swarthmore College, Swarthmore, PA, 19081, USA

    Katherine R. Meckel

  4. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

    Sierra S. Simpson & Olivier George

  5. Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Atrium Wake Forest Baptist Health, Winston-Salem, NC, 27101, USA

    Emily G. Peck, Jonathon P. Sens, Rebecca S. Hofford & Drew D. Kiraly

  6. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA

    Michael Z. Leonard & Erin S. Calipari

  7. Vanderbilt Brain Institute, Vanderbilt University, 865F Light Hall, 2215 Garland Avenue, Nashville, TN, 37232, USA

    Erin S. Calipari

  8. Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, USA

    Erin S. Calipari

  9. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA

    Erin S. Calipari

  10. Department of Psychiatry and Behavioral Sciences, Vanderbilt University, Nashville, TN, USA

    Erin S. Calipari

  11. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Rebecca S. Hofford & Drew D. Kiraly

  12. Department of Psychiatry, Wake Forest University School of Medicine, Atrium Wake Forest Baptist Health, Winston-Salem, NC, 27101, USA

    Drew D. Kiraly

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  1. Katherine R. Meckel
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Contributions

DDK, ESC, and KRM designed the experiments. KRM, AG, EGP, ESC, RSH, and DDK performed experiments. KRM, SSS, AG, JSP, MZL, OG, ESC, RSH & DDK analyzed data. KRM & DDK wrote the manuscript. All authors provided critical edits and feedback of the finalized manuscript.

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Correspondence to Drew D. Kiraly.

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Meckel, K.R., Simpson, S.S., Godino, A. et al. Microbial short-chain fatty acids regulate drug seeking and transcriptional control in a model of cocaine seeking. Neuropsychopharmacol. 49, 386–395 (2024). https://doi.org/10.1038/s41386-023-01661-w

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