It will be important next to try and tease apart the relationships between α3/α5/β4 variants on one hand and the etiology of nicotine dependence and of lung cancer on the other. It is reasonable to propose that nicotine dependence is partly responsible for the observed smoking associated pathology (Figure 1c), and that the increased risk of lung cancer is a good example of gene by environment interaction. This notion is supported by the behavioral phenotype of α5 subunit knock-out mice, which display very low sensitivity to nicotine-induced behaviors and seizures10 and fail to display the withdrawal signs normally seen after discontinuation of chronic nicotine.11 Taken together, these findings suggest that α5 plays an important role in the short- and long-term psychoactive effects of nicotine.
