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

Autor: Meckel KR; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Department of Biology, Swarthmore College, Swarthmore, PA, 19081, USA., Simpson SS; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA., Godino A; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Peck EG; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Atrium Wake Forest Baptist Health, Winston-Salem, NC, 27101, USA., Sens JP; Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Atrium Wake Forest Baptist Health, Winston-Salem, NC, 27101, USA., Leonard MZ; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA., George O; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA., Calipari ES; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.; Vanderbilt Brain Institute, Vanderbilt University, 865F Light Hall, 2215 Garland Avenue, Nashville, TN, 37232, USA.; Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, USA.; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.; Department of Psychiatry and Behavioral Sciences, Vanderbilt University, Nashville, TN, USA., Hofford RS; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Atrium Wake Forest Baptist Health, Winston-Salem, NC, 27101, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Kiraly DD; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. dkiraly@wakehealth.edu.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. dkiraly@wakehealth.edu.; Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Atrium Wake Forest Baptist Health, Winston-Salem, NC, 27101, USA. dkiraly@wakehealth.edu.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. dkiraly@wakehealth.edu.; Department of Psychiatry, Wake Forest University School of Medicine, Atrium Wake Forest Baptist Health, Winston-Salem, NC, 27101, USA. dkiraly@wakehealth.edu.
Jazyk: angličtina
Zdroj: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology [Neuropsychopharmacology] 2024 Jan; Vol. 49 (2), pp. 386-395. Date of Electronic Publication: 2023 Aug 02.
DOI: 10.1038/s41386-023-01661-w
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)
Databáze: MEDLINE
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