The nicotine found in tobacco stimulates the reward circuit, encouraging consumption and potentially leading to addiction. In a paper published in
Neuron, scientists reveal how, in mice, a small region of the brain called the interpeduncular nucleus acts as a natural brake on the reward circuit. This brake, whose mechanism they describe, reduces the animals' attraction to nicotine.
When the nicotine in tobacco is inhaled, it acts on several structures of the nervous system. More specifically, it activates neurons in a specific area of the brain called the ventral tegmental area (VTA). This region is part of what is known as the reward system.
The activation of these neurons triggers the release of dopamine, a chemical messenger that reinforces reward-seeking behaviors. This mechanism can potentially lead to nicotine addiction.
Discovery of a natural regulatory mechanism for nicotine addiction
In a study published in the journal
Neuron, scientists focused on a small brain region called the interpeduncular nucleus (IPN). This region is particularly rich in specific nicotine receptors called b4-type nicotinic receptors.
By developing a chemogenetic technique in genetically modified mice, they managed to deactivate these nicotinic receptors only in this brain region. They then observed that this deactivation made nicotine more attractive and amplified the VTA's response to the drug. This discovery shows that the IPN acts as a brake on nicotine via b4-type nicotinic receptors.
However, the IPN is not directly connected to the VTA. To understand how this brake works, the scientists used another technique, optogenetics, which allows controlling neuron activity with light. They discovered that the IPN influences another group of neurons located in a region called the LDTg to modulate the attraction to nicotine. This relay thus appears essential to the braking effect.
These results reveal a natural regulatory mechanism for the addictive effect of nicotine. They show that the nervous system does not just reinforce reward-seeking behaviors but also has mechanisms to curb them.
A - Chemogenetic method: the b4-type nicotinic receptor is mutated to insert a cysteine near the nicotine binding site. A specific ligand attaches to this cysteine and durably inhibits the receptor.
B - In the absence of the ligand, low-dose nicotine strongly activates the IPN but not the VTA, and remains minimally attractive.
C - After ligand attachment, the IPN is inhibited, and the VTA is activated by nicotine, which becomes attractive even at low doses.
© Alexandre Mourot Jehl J, Ciscato M, Vicq E, et al. The interpeduncular nucleus blunts the rewarding effect of nicotine.
Neuron. Published online April 16, 2025. doi:
10.1016/j.neuron.2025.03.035