Tiny worm provides model for the genetics of nicotine dependence

This finding should allow researchers to better understand how nicotine dependence works, and perhaps devise new ways to block the craving that keeps humans smoking cigarettes. Nicotine is the addictive substance in tobacco. Dependence on nicotine drives many of the most preventable causes of death in the U.S. and is a worldwide health problem.

A team led by X.Z. Shawn Xu, assistant research professor at the Life Sciences Institute and assistant professor of physiology at U-M Medical School, has completed a series of experiments which establish that C. elegans can get hooked on nicotine. Like humans, the nicotine-sensitive worms showed acute responses to nicotine exposure, as well as tolerance, sensitization and withdrawal.

“It turns out that worms exhibited behavioral responses to nicotine that parallel those observed in mammals,” said Xu, whose name is pronounced Shoo. “But it is much easier to identify novel functions of a gene in worms.”

Xu and his team found that the genes known to underlie nicotine dependence in mammals are also present in the worms. Having established worms as a model, the Xu team then tried to identify new genes important for nicotine dependence. They found for the first time that TRP channel genes which enable cells to respond to various external stimuli are a part of the nicotine response.

In fact, when they knocked the TRP gene out of worms, the animals no longer responded to nicotine exposures. But when a new generation of worms had that missing gene replaced by a human version of the TRP gene, the worms returned to being nicotine-sensitive.

“This demonstrates that human TRP genes have the capacity to mediate nicotine dependence, suggesting that human TRP genes are important for nicotine dependence in humans,” Xu said.

It also makes TRP genes a potential target for the development of drugs to treat tobacco addiction, and the worms can help in that research. C. elegans can also be used to find other unknown genes critical for nicotine dependence.