Cigarette and other tobacco smoking are responsible for millions of deaths worldwide each year. Nicotine drives addiction to tobacco, and the brain’s reaction to it is complex.
When people or animals use nicotine, they tend to like it at lower doses but dislike it at higher doses. This creates a pattern where small amounts feel good and encourage more use, while large amounts feel bad and make them want to stop. Scientists are still trying to figure out exactly what drives this effect in the brain.
Now a study led by Huanghe Yang, PhD, associate professor of biochemistry, has identified a previously unknown “emergency brake” that neurons in a particular area of the brain (MHb neurons) use to protect themselves from becoming overly active when exposed to nicotine. The finding suggests that scientists could leverage that mechanism to reduce nicotine’s addictive power.
“Our discovery significantly advances the understanding of how the brain responds to nicotine, opening new possibilities for treating nicotine addiction,” Yang said. “By uncovering how MHb neurons naturally resist overstimulation, we can now explore targeted therapies that mimic or enhance this protective response, potentially helping smokers quit or preventing nicotine dependence altogether.”
The work is published March 19, 2025, in the journal Science Advances.
Studying mice, the researchers found that neurons in the medial habenula (MHb) employ a unique process called a “long-lasting refractory period” when exposed to high doses of nicotine. This process involves specific chloride channels known as TMEM16A calcium-activated chloride channels, Yang said, working together with calcium channels in a coordinated way that has never been documented in any other brain region.
The finding points the way toward future research to develop medications aimed at leveraging this protective behavior of the MHb neurons. In addition, further studies are needed to find out if other neuron types involved in disease use this long-lasting refractory period mechanism, Yang said.
The discovery resulted from a collaboration with Duke colleague Henry Yin, PhD, a professor of psychology and neuroscience and a professor in neurobiology, as well as Takafumi Kawai, PhD, an assistant professor at Osaka University in Japan.
This work was funded by the Holland-Trice Scholars Award, the US-Japan Brain Research Cooperative Program, and the Grant-in-Aid Fund for the Promotion of Joint International Research.