New scientific developments can improve our understanding of nicotine addiction and spur the development of better prevention and treatment strategies.
Genetics and Epigenetics
An estimated 50-75 percent of the risk for nicotine addiction is attributable to genetic factors.221 A cluster of genes (CHRNA5-CHRNA3-CHRNB4) on chromosome 15 that encode the α5, α3, and β4 protein subunits that make up the brain receptor for nicotine221–223 are particularly implicated in nicotine dependence and smoking among people of European descent. Variation in the CHRNA5 gene influences the effectiveness of combination NRT, but not varenicline.224 Other research has identified genes that influence nicotine metabolism and therefore, the number of cigarettes smoked,225 responsiveness to medication,204,205 and chances of successfully quitting.226 For example, the therapeutic response to varenicline is associated with variants for the CHRNB2, CHRNA5, and CHRNA4 genes, while bupropion-related cessation is linked with variation in genes that affect nicotine metabolism.227
Smoking can also lead to persistent changes in gene expression (epigenetic changes), which may contribute to associated medical consequences over the long term, even following cessation.228 Epigenetic changes may serve as a potential biomarker for prenatal tobacco smoke exposure. Researchers found tobacco-specific changes at 26 sites on the epigenome, and this pattern predicted prenatal exposure with 81 percent accuracy.229 A large scale meta-analysis of data on epigenetic changes associated with prenatal exposure to cigarette smoke also identified many epigenetic changes that persisted into later childhood.230 More research is needed to understand the long-term health impacts of these changes.
Cutting-edge neuroimaging technologies have identified brain changes associated with nicotine dependence and smoking. Using functional magnetic resonance imaging (fMRI), scientists can visualize smokers’ brains as they respond to cigarette-associated cues that can trigger craving and relapse.231 Such research may lead to a biomarker for relapse risk and for monitoring treatment progress, as well as point to regions of the brain involved in the development of nicotine addiction.29
A neuroimaging technology called default-mode or resting-state fMRI (rs-fMRI) reveals intrinsic brain activity when people are alert but not performing a particular task. Using this technique, researchers are examining the neurobiological profile associated with withdrawal and how nicotine impacts cognition.232 Comparisons between smokers and nonsmokers suggest that chronic nicotine may weaken connectivity within brain circuits involved in planning, paying attention, and behavioral control—possibly contributing to difficulty with quitting.233 fMRI studies also reveal the impact of smoking cessation medications on the brain—particularly how they modulate the activity of different brain regions to alleviate withdrawal symptoms and reduce smoking. A review of these studies suggested that NRT enhances cognition during withdrawal by modulating activity in default-network regions, but may not affect neural circuits associated with nicotine addiction.234
Some imaging techniques allow researchers to visualize neurotransmitters and their receptors, further informing our understanding of nicotine addiction and its treatment.27 Using these techniques, researchers have established that smoking increases the number of brain receptors for nicotine. Individuals who show greater receptor upregulation are less likely to stop smoking.28 Combining neuroimaging and genetics may yield particularly useful information for improving and tailoring treatment. For example, nonsmoking adolescents with a particular variant in the CHRNA5-CHRNA3-CHRNB4 gene cluster (which is associated with nicotine dependence and smoking) showed reduced brain activity in response to reward in the striatum as well as the orbitofrontal and anterior cingulate cortex. This finding suggests that genetics can influence how the brain processes rewards which may influence vulnerability to nicotine dependence.235 Neuroimaging genetics also shows that other genes, including ones that influence dopamine neurotransmission, influence reward sensitivity and risk for addiction to nicotine.236