Our findings reveal the habenulo-interpeduncular pathway as a key neurocircuit controlling nicotine intake. This circuit acts in a manner opposite to the mesoaccumbens `positive reward' pathway and instead transmits an inhibitory motivational signal that limits nicotine intake. There are reciprocal projections between the MHb and portions of the caudomedial VTA (interfascicular nucleus), with the VTA and IPN projecting to many common brain areas including the dorsal tegmental nucleus, raphé nuclei and dorsomedial nucleus of thalamus. Hence, it will be important to determine if direct cross-talk between VTA and IPN, or integration of reward-related information from these structures at downstream brain sites47, is responsible for regulating the motivational salience of nicotine and coordinating behavioral output. Our data suggest that individuals carrying risk alleles for tobacco dependence resulting in deficient α5* nAChR function are relatively insensitive to inhibitory effects of nicotine on reward pathways, consequently extending the range of nicotine doses that have net stimulatory effects on reward systems. Such a scenario is likely to be most important in the acquisition of the tobacco habit in which experiencing a negative effect of
