A study of CHRNA5 knock-out mice showed that re-expressing this gene in the medial habenula, which extends projections to a brain region shown to mediate nicotine withdrawal,44 abolished the inhibitory effects of nicotine while maintaining the reinforcing effects of nicotine.45 In a functional magnetic resonance study of smokers, genetic variation in CHRNA5 appeared to also affect reactivity to smoking cues in the insula, hippocampus and dorsal striatum, regions implicated in addictive behavior and memory.46 Thus, it is biologically plausible that rs2036527, as a correlate of increased expression of the CHRNA5 gene, could be associated with smoking quantity as a consequence of neuro-adaptations resulting from complex interactions between genes and environment that alter positive and negative reinforcement.47
