Mechanisms that underlie the two distinct association results involving rs1051730 can be postulated based on recent studies in neurogenetics, neuroscience, and pharmacology. α5 knockout mice self-administer nicotine more vigorously than wild-type mice [73], show reduced seizure and hyperlocomotive sensitivity to nicotine [74], and exhibit conditioned place preference for nicotine at doses that are aversive in wildtype mice [75]. These properties are thought to be due to the α5 subunit regulation of the medial habenular-interpeduncular nuclear tract [73]. Functional magnetic resonance imaging in healthy human smokers has characterized functional connectivity (circuits) [76], including a dorsal anterior cingulate cortex to ventral striatal circuit inversely associated with FTND and multiple distinct intra-cingulate cortex and cingulate cortex to frontal region circuits strengthened by nicotine patch administration. In additional studies in smokers and non-smokers, and in individuals who do and who do not meet criteria for Axis I disorders [26], rs16969968 (highly correlated with rs1051730 in European ancestry populations, and coding for CHRNA5 p.Asp398Asn, where Asn398 is associated with reduced nAChR function [77]) was observed to be associated with functional connectivity within the same FTND-associated
