Researchers found that a previously dismissed genetic mechanism may contribute to nicotine dependence, and to the withdrawal effects that can make quitting smoking so difficult.
Scientists examined withdrawal responses in the millimeter-long roundworms Caenorhabditis elegans, which get hooked on nicotine just like humans.
In the findings published in Cell Reports, the researchers identified specific genes and microRNA that play an essential role in how the roundworms develop nicotine dependence and withdrawal responses--clues that may carry over to the mammalian realm.
The study took a fresh look at a previously dismissed biological mechanism. Most research in the field has focused on how proteins called nicotine acetylcholine receptors contribute to dependence.
The team focused on an earlier step in the genetic coding process and discovered that a series of genes were involved in a process that ultimately increased the production of the nicotine receptor proteins, with microRNAs--a class of small RNA molecules that help fine-tune gene expression--playing a pivotal role.
Authors show that the nAChR gene acr-19 and alg-1, a key Argonaute-family member in the microRNA machinery, are specifically required for nicotine withdrawal response following chronic nicotine treatment. Chronic exposure to nicotine downregulates alg-1, leading to upregulation of acr-19. This effect is mediated by the microRNA miR-238 that recognizes the 3′ UTR of acr-19 transcript.
"We're seeing a clear link between nicotine, microRNA, the receptor proteins, and nicotine-dependent behavior," said one of the lead authors on the study.
This mechanism had been dismissed as unimportant to nicotine dependence. However, senior author pointed out, those conclusions were made decades ago, using less sophisticated techniques.
The lab previously demonstrated that the worms exhibit behavioral responses to nicotine similar to what mammals experience, and that some of the genes involved in nicotine dependence in worms are conserved in mammals--meaning the worms are a good genetic and behavioral model for studying nicotine dependence.
Authors hope that this latest discovery in C. elegans will now lead other scientists to re-examine the role of these microRNAs in nicotine dependence in mammals, and ultimately lead to a better understanding of what causes the dependence.