Impact of the gut microbiome on nicotine’s motivational effects and glial cells in the ventral tegmental area in male mice
Neuropsychopharmacol.. 2023-03-17; 48(6): 963-974
DOI: 10.1038/s41386-023-01563-x
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Lakosa A(#)(1), Rahimian A(#)(1), Tomasi F(#)(1)(2), Marti F(3)(4), Reynolds LM(3), Tochon L(5)(6), David V(5)(6), Danckaert A(7), Canonne C(1), Tahraoui S(1), de Chaumont F(8), Forget B(1)(8), Maskos U(1), Besson M(9).
Author information:
(1)Institut Pasteur, Université Paris Cité, Neurobiologie Intégrative des
Systèmes Cholinergiques, CNRS UMR 3571, Paris, France.
(2)Neuroscience Paris Seine, Sorbonne Université, INSERM, CNRS, 75005 Paris,
France.
(3)Plasticité du Cerveau, CNRS UMR 8249, ESPCI Paris, Université PSL, Paris,
France.
(4)Neuroscience Paris Seine, Sorbonne Université, INSERM, CNRS, 75005, Paris,
France.
(5)Université de Bordeaux, Bordeaux, France.
(6)CNRS UMR 5287, Institut de Neurosciences Cognitives et Intégratives
d’Aquitaine, Bordeaux, France.
(7)UTechS Photonics Bioimaging/C2RT, Institut Pasteur, Université Paris Cité, 25
rue du Dr Roux, 75724, Paris Cedex 15, France.
(8)Génétique humaine et fonctions cognitives, CNRS UMR 3571, Institut Pasteur,
Université Paris Cité, 25 rue du Dr Roux, 75724, Paris Cedex 15, France.
(9)Institut Pasteur, Université Paris Cité, Neurobiologie Intégrative des
Systèmes Cholinergiques, CNRS UMR 3571, Paris, France.
.
(#)Contributed equally
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.
© 2023. The Author(s), under exclusive licence to American College of
Neuropsychopharmacology.
DOI: 10.1038/s41386-023-01563-x
PMCID: PMC10156728
PMID: 36932179 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests.