Microbiome Depletion Increases Fentanyl Self-Administration and Alters the Striatal Proteome Through Short-Chain Fatty Acids.
| Autor: | Hofford RS; Department of Translational Neuroscience, Wake Forest School of Medicine, Winston-Salem, NC 27101.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NewYork, NY 10029.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NewYork, NY 10029., Meckel KR; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NewYork, NY 10029.; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, NewYork, NY 10029., Wiser EJ; Department of Translational Neuroscience, Wake Forest School of Medicine, Winston-Salem, NC 27101., Wang W; Keck MS & Proteomics Resource, Yale University School of Medicine, New Haven, CT 06520., Sens JP; Department of Translational Neuroscience, Wake Forest School of Medicine, Winston-Salem, NC 27101., Kim M; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NewYork, NY 10029.; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, NewYork, NY 10029., Godino A; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NewYork, NY 10029.; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, NewYork, NY 10029., Lam TT; Keck MS & Proteomics Resource, Yale University School of Medicine, New Haven, CT 06520.; Yale/NIDA Neuroproteomics Center, Yale University School of Medicine, New Haven, CT 06520.; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520., Kiraly DD; Department of Translational Neuroscience, Wake Forest School of Medicine, Winston-Salem, NC 27101 dkiraly@wakehealth.edu.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NewYork, NY 10029.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NewYork, NY 10029.; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, NewYork, NY 10029.; Department of Psychiatry, Atrium Health Wake Forest Baptist, Winston-Salem, NC 27101. |
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| Jazyk: | angličtina |
| Zdroj: | ENeuro [eNeuro] 2024 Feb 15; Vol. 11 (2). Date of Electronic Publication: 2024 Feb 15 (Print Publication: 2024). |
| DOI: | 10.1523/ENEURO.0388-23.2023 |
| Abstrakt: | Opioid use disorder (OUD) is a public health crisis currently being exacerbated by increased rates of use and overdose of synthetic opioids, primarily fentanyl. Therefore, the identification of novel biomarkers and treatment strategies to reduce problematic fentanyl use and relapse to fentanyl taking is critical. In recent years, there has been a growing body of work demonstrating that the gut microbiome can serve as a potent modulator of the behavioral and transcriptional responses to both stimulants and opioids. Here, we advance this work to define how manipulations of the microbiome drive fentanyl intake and fentanyl-seeking in a translationally relevant drug self-administration model. Depletion of the microbiome of male rats with broad spectrum antibiotics leads to increased drug administration on increased fixed ratio, progressive ratio, and drug seeking after abstinence. Utilizing 16S sequencing of microbiome contents from these animals, specific populations of bacteria from the gut microbiome correlate closely with levels of drug taking. Additionally, global proteomic analysis of the nucleus accumbens following microbiome manipulation and fentanyl administration to define how microbiome status alters the functional proteomic landscape in this key limbic substructure. These data demonstrate that an altered microbiome leads to marked changes in the synaptic proteome in response to repeated fentanyl treatment. Finally, behavioral effects of microbiome depletion are reversible by upplementation of the microbiome derived short-chain fatty acid metabolites. Taken together, these findings establish clear relevance for gut-brain signaling in models of OUD and lay foundations for further translational work in this space. (Copyright © 2024 Hofford et al.) |
| Databáze: | MEDLINE |
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