Nicotine disrupts top down habenular control over cholinergic inputs to the ventral tegmental area to increase motivational valence of food rewards
Biological Psychiatry. 2025-07-01; :
DOI: 10.1016/j.biopsych.2025.06.036
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https://www.bordeaux-neurocampus.fr/11904
Campos RC(1), Marti F(2), Rigoni D(1), Fofo H(1), Pousinha P(1), Ortiz V(1), Royon L(1), Violain M(1), Heck N(3), Faure P(2), Soiza-Reilly M(4), Fernandez SP(1), Barik J(5).
Author information:
(1)CNRS – UMR7275, Institut de Pharmacologie Moléculaire et Cellulaire,
Valbonne, France; Université Côte d’Azur, 06560 Nice, France; Inserm U1323.
(2)CNRS – UMR8249, ESPCI, Paris, France.
(3)CNRS – UMR8246, Université Pierre et Marie Curie, Paris, France.
(4)Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE –
CONICET), Universidad de Buenos Aires, Argentina.
(5)CNRS – UMR7275, Institut de Pharmacologie Moléculaire et Cellulaire,
Valbonne, France; Université Côte d’Azur, 06560 Nice, France; Inserm U1323.
Electronic address: .
BACKGROUND: Tobacco use significantly impacts reward-driven behavior, leading to
comorbidities across a lifetime. While the addictive properties of nicotine are
well-studied, its effects on cellular mechanisms beyond drug-seeking behaviors
remain elusive. Here we investigate the circuit alterations that parallel
drug-related behaviors.
METHODS: Male mice were chronically exposed to nicotine in their drinking water
for 6 weeks. We then combined behavioral measures in operant and non-operant
tasks to evaluate changes in motivation while employing chemogenetics to
selectively modulate cholinergic inputs to the ventral tegmental area (VTA). We
combined patch clamp with optogenetics and in vivo electrophysiological
recordings to provide a comprehensive cellular analysis of nicotine’s impact.
Functional assessments were paralleled with high-resolution array tomography to
monitor structural adaptations.
RESULTS: Chronic nicotine dampened the cholinergic modulation of VTA dopamine
(DA) neuron activity, leading to an exaggerated motivation for food reward
seeking. Selective chemogenetic enhancement of cholinergic tone from the
laterodorsal tegmentum (LDT) to the VTA restored normal motivational control,
while silencing of this projection triggered the opposite effect. We reveal
structural and functional deficits in the synaptic integration of excitatory
inputs from the lateral habenula onto LDT cholinergic neurons projecting to the
VTA that correlate with observed behavioral alterations. We identify specific
cellular and synaptic changes underlying nicotine-induced dysregulation of
motivation.
CONCLUSIONS: Chronic nicotine consumption alters motivation for natural rewards
by disrupting a top-down control of the lateral habenula onto the LDT-VTA
cholinergic axis. It highlights previously unrecognized contributors to
nicotine’s impact on mental health.
Copyright © 2025. Published by Elsevier Inc.
DOI: 10.1016/j.biopsych.2025.06.036
PMID: 40659199