Here, we investigated the role of α5* nAChRs in the reinforcing properties of nicotine. We found that wildtype and knockout mice responded for intravenously self-administered nicotine infusions according to an inverted U-shaped dose-response curve, consistent with previous reports in humans18, non-human primates19, dogs20 and rats21. However, the knockout mice responded far more vigorously than wildtype mice for nicotine infusions, especially when higher unit doses were available (Fig. 1a); see Ref.22. Increased responding for nicotine in knockout mice was not secondary to alterations in operant performance or the motivational salience of reward-paired conditioned stimuli (Supplementary Fig. 1). When we calculated total amounts of nicotine consumed at each dose available for self-administration, we found that wildtype mice titrated their responding to consume ~1.5 mg kg−1 per session (Fig. 1b); which achieves plasma concentrations of nicotine comparable to those detected in humans after 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
