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Impact of the gut microbiome on nicotine’s motivational effects and glial cells in the ventral tegmental area in male mice

Neuropsychopharmacology volume 48, pages 963–974 (2023)Cite this article

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Abstract

A link between gut dysbiosis and the pathogenesis of brain disorders has been identified. A role for gut bacteria in drug reward and addiction has been suggested but very few studies have investigated their impact on brain and behavioral responses to addictive drugs so far. In particular, their influence on nicotine’s addiction-like processes remains unknown. In addition, evidence shows that glial cells shape the neuronal activity of the mesolimbic system but their regulation, within this system, by the gut microbiome is not established. We demonstrate that a lack of gut microbiota in male mice potentiates the nicotine-induced activation of sub-regions of the mesolimbic system. We further show that gut microbiota depletion enhances the response to nicotine of dopaminergic neurons of the posterior ventral tegmental area (pVTA), and alters nicotine’s rewarding and aversive effects in an intra-VTA self-administration procedure. These effects were not associated with gross behavioral alterations and the nicotine withdrawal syndrome was not impacted. We further show that depletion of the gut microbiome modulates the glial cells of the mesolimbic system. Notably, it increases the number of astrocytes selectively in the pVTA, and the expression of postsynaptic density protein 95 in both VTA sub-regions, without altering the density of the astrocytic glutamatergic transporter GLT1. Finally, we identify several sub-populations of microglia in the VTA that differ between its anterior and posterior sub-parts, and show that they are re-organized in conditions of gut microbiota depletion. The present study paves the way for refining our understanding of the pathophysiology of nicotine addiction.

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Fig. 1: Antibiotic-induced or constitutive gut microbiota depletion enhances nicotine-induced activation of the mesolimbic system.
Fig. 2: Gut microbiota depletion enhances nicotine-evoked responses of dopaminergic neurons of the posterior ventral tegmental area.
Fig. 3: Gut microbiota depletion modifies nicotine’s motivational effects without altering nicotine withdrawal syndrome.
Fig. 4: Gut microbiota depletion increases astrocyte and post-synaptic protein, but not GLT1, density in the ventral tegmental area.
Fig. 5: Distinct microglial sub-populations are present in the anterior and posterior ventral tegmental area, and their distribution is re-organized in conditions of gut microbiota depletion.

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Acknowledgements

We thank the Biomics and gnotobiology plateforms and animal facilities (Institut Pasteur, Paris).

Funding

This work was supported by the Institut Pasteur, Paris (GPF Microbes and Brain, project “µBIOTADDICT”). UtechS PBI/C2RT is part of the France BioImaging infrastructure supported by the French National Research Agency (ANR-10-INSB-04-01, “Investments for the future”) and is supported by Conseil de la Region Ile-de-France (Domaine d’Intérêt Majeur DIM1HEALTH) and by Fondation Française pour la Recherche Médicale (Programme Grands Equipements).

Author information

Author notes

  1. Flavio Tomasi

    Present address: Neuroscience Paris Seine, Sorbonne Université, INSERM, CNRS, 75005 Paris, France

  2. Benoît Forget

    Present address: Génétique humaine et fonctions cognitives, CNRS UMR 3571, Institut Pasteur, Université Paris Cité, 25 rue du Dr Roux, 75724, Paris Cedex 15, France

  3. These authors contributed equally: Alina Lakosa, Anaïs Rahimian, Flavio Tomasi.

Authors and Affiliations

  1. Institut Pasteur, Université Paris Cité, Neurobiologie Intégrative des Systèmes Cholinergiques, CNRS UMR 3571, Paris, France

    Alina Lakosa, Anaïs Rahimian, Flavio Tomasi, Candice Canonne, Sylvana Tahraoui, Benoît Forget, Uwe Maskos & Morgane Besson

  2. Plasticité du Cerveau, CNRS UMR 8249, ESPCI Paris, Université PSL, Paris, France

    Fabio Marti & Lauren M. Reynolds

  3. Neuroscience Paris Seine, Sorbonne Université, INSERM, CNRS, 75005, Paris, France

    Fabio Marti

  4. Université de Bordeaux, Bordeaux, France

    Léa Tochon & Vincent David

  5. CNRS UMR 5287, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, Bordeaux, France

    Léa Tochon & Vincent David

  6. UTechS Photonics Bioimaging/C2RT, Institut Pasteur, Université Paris Cité, 25 rue du Dr Roux, 75724, Paris Cedex 15, France

    Anne Danckaert

  7. Génétique humaine et fonctions cognitives, CNRS UMR 3571, Institut Pasteur, Université Paris Cité, 25 rue du Dr Roux, 75724, Paris Cedex 15, France

    Fabrice de Chaumont

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MB, AD, VD, BF, FM, UM designed research; MB, CC, VD, AL, FM, AR, LR, ST, LT, and FT performed research; FDC contributed new analytic tools; MB, CC, AD, VD, AL, FM, AR, LR, ST, LT, and FT analyzed data; MB wrote the original draft of the paper. All co-authors read, reviewed, edited and approved the final manuscript.

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Correspondence to Morgane Besson.

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Lakosa, A., Rahimian, A., Tomasi, F. et al. Impact of the gut microbiome on nicotine’s motivational effects and glial cells in the ventral tegmental area in male mice. Neuropsychopharmacol. 48, 963–974 (2023). https://doi.org/10.1038/s41386-023-01563-x

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