Nicotine engages a VTA-NAc feedback loop to inhibit amygdala-projecting dopamine neurons and induce anxiety-like behaviors

Tïnaïg Borgne, Claire Nguyen, Eléonore Vicq, Joachim Jehl, Clément Solié, Nicolas Guyon, Louison Daussy, Aylin Gulmez, Lauren M. Reynolds, Sarah Mondoloni, Stéfania Tolu, Stéphanie Pons, Uwe Maskos, Emmanuel Valjent, Alexandre Mourot, Philippe Faure () and Fabio Marti ()
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Tïnaïg Borgne: École supérieure de physique et de chimie industrielles de la Ville de Paris (ESPCI Paris)
Claire Nguyen: Sorbonne Université
Eléonore Vicq: École supérieure de physique et de chimie industrielles de la Ville de Paris (ESPCI Paris)
Joachim Jehl: École supérieure de physique et de chimie industrielles de la Ville de Paris (ESPCI Paris)
Clément Solié: École supérieure de physique et de chimie industrielles de la Ville de Paris (ESPCI Paris)
Nicolas Guyon: École supérieure de physique et de chimie industrielles de la Ville de Paris (ESPCI Paris)
Louison Daussy: École supérieure de physique et de chimie industrielles de la Ville de Paris (ESPCI Paris)
Aylin Gulmez: École supérieure de physique et de chimie industrielles de la Ville de Paris (ESPCI Paris)
Lauren M. Reynolds: École supérieure de physique et de chimie industrielles de la Ville de Paris (ESPCI Paris)
Sarah Mondoloni: Sorbonne Université
Stéfania Tolu: Sorbonne Université
Stéphanie Pons: Institut Pasteur
Uwe Maskos: Institut Pasteur
Emmanuel Valjent: Université de Montpellier, INSERM U1298
Alexandre Mourot: École supérieure de physique et de chimie industrielles de la Ville de Paris (ESPCI Paris)
Philippe Faure: École supérieure de physique et de chimie industrielles de la Ville de Paris (ESPCI Paris)
Fabio Marti: École supérieure de physique et de chimie industrielles de la Ville de Paris (ESPCI Paris)

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Nicotine activates ventral tegmental area (VTA) dopaminergic (DA) neurons projecting to the nucleus accumbens (NAc) to drive its reinforcing effects. Simultaneously, nicotine inhibits those projecting to the amygdala (Amg) to mediate anxiety-like behavior through a process that remains unknown. Here, we show that in male mice, NAc- and Amg-projecting DA neurons respond with similar polarities to ethanol and nicotine, suggesting a shared network-based mechanism underlying the inhibitory effect of these otherwise pharmacologically-distinct drugs. Selective activation of NAc-projecting DA neurons, using genetic or optogenetic strategies, produced inhibition of Amg-projecting DA neurons, through a GABAergic feedback loop. Furthermore, optogenetically silencing this feedback loop prevented nicotine from inducing both inhibition of DA neurons and anxiety-like behavior. Therefore, nicotine-induced inhibition of the VTA-Amg DA pathway results from a VTA-NAc inhibitory feedback loop, mediating anxiety-like behavior.

Date: 2025
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DOI: 10.1038/s41467-025-61180-8

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