Risk-related polymorphisms in CHRNA5-A3-B4 have been associated with individual differences in corticostriatal circuit reactivity to nicotine cues as well as resting state connectivity. The risk (i.e., A) allele of rs16969968 predicts reduced reactivity in corticostriatal circuit nodes (e.g., dorsal striatum, hippocampus, insula) in response to smoking cues among nicotine-dependent women. Notably, because smoking is associated with enhanced smoking cue reactivity, these results suggest a dissociation between CHRNA5-A3-B4 genetic risk and neural correlates of smoking. While the reasons for this dissociation are unclear, the authors speculate that risk allele carriers may form relatively poorer drug-cue associations and that stronger cue-related memory may be needed to promote continued smoking in those with relatively lower genetic risk. Another possible interpretation of these data is that because the risk allele at rs16969968 is associated with decreased response to a nicotine agonist [47], independent smoking-related cues may not develop the same predictive value for risk allele carriers, who may need to ingest relatively larger dosages to obtain reward. The risk allele of rs16969968 may confer vulnerability to smoking via blunted corticostriatal response to smoking cues, or via other, not mutually exclusive neural mechanisms, such as neural reactivity to threat [97].
