5 h of smoking their preferred brand of cigarette23,24. In contrast, knockout mice did not titrate their responding and consumed greater amounts of nicotine as the dose increased (Fig. 1b). Knockout mice also had greater motivation to seek and obtain nicotine when tested under a progressive ratio schedule of reinforcement, an effect most apparent again at high doses (Supplementary Fig. 2). Enhanced responding for nicotine as the unit dose increases is thought to reflect an intensification of the reinforcing properties of the drug, thereby motivating higher levels of intake25. Diminished responding as the dose increases reflects greater restraint over intake to avoid the increasingly aversive effects of higher drug doses18,25 or more rapid development of drug satiation25,26. Our findings therefore suggest that deletion of α5 nAChR subunits has a dissociable effect on the motivational drives that control nicotine intake. The stimulatory effects of nicotine on brain reinforcement systems (i.e., ascending portion of dose-response curve) are unaltered by α5 subunit knockout, since the wildtype and knockout mice responded for nicotine at a similar maximal rate. Instead, deficient α5* nAChR signaling appears to attenuate the negative effects of nicotine that limit its intake (i.e., descending portion of dose-response curve). These findings are
