These results show that CHRNA5-A3-B4 haplotypes are consistently related to severity of nicotine dependence among long-term smokers of European-American descent who began daily smoking at or before age 16 but not among those who began smoking daily after age 16. The robustness of the genotype by age of onset interaction is supported by the fact that there was a significant interaction between the two variables in logistic regression analyses and by the fact that significant associations between genetic variants and dependence were specific to early onset smokers in all three cohorts. Both human and animal research shows that early vs. late smoking or nicotine exposure is associated with more severe nicotine dependence, or greater nicotine self-administration, manifested in adulthood [25], [45]–[47] and that adolescence is a period of heightened sensitivity to nicotine reward as well as decreased sensitivity to nicotine's aversive actions [47]–[50]. Animal research suggests possible mechanisms for this effect related to persistent changes in brain structure and function. For instance, significantly greater high affinity nicotinic receptor binding is observed in the midbrain and striatum of adolescent versus adult
