Nicotine (NIC) has two reinforcement-related effects that may contribute to dependence: 1) NIC acts as a primary reinforcer, and 2) NIC, non-associatively, enhances reinforcement from concur- rently available nonpharmacological stimuli. Varenicline (VAR), a partial agonist at nicotinic re- ceptors, is one of the most effective smoking cessation pharmacotherapies. Previous findings from our laboratory show that VAR mimics the reinforcement-enhancing effects of NIC. The present study sought to determine the role of these effects in a self-administration paradigm, in which rats were able to lever press for intravenous VAR and/or a moderately reinforcing visual stimulus (VS). For five groups of rats (i.e., the 2-lever groups), responding on one lever was reinforced with VAR (0.01, 0.06 or 0.1 mg/kg/infusion), NIC (0.06 mg/kg/infusion) or saline (SAL), while responding on a separate lever was reinforced with the VS. Three additional groups were reinforced for pressing a single, active lever and received contingent VAR paired with the VS, the VS only (while receiving noncontingent [i.e., yoked] VAR) or VAR only (all doses 0.1 mg/kg/infusion). Responding was maintained on an FR1 for five sessions, an FR2 for six sessions and an FR5 for fifteen sessions. Compared to responding for the VS in the 2-lever SAL group, responding on the active lever was significantly higher in the contingent VAR + VS group but was not significantly higher in the noncontingent VAR + VS group. Responding for VAR only was not significantly different than responding for SAL only in the 2-lever SAL group. Across the 2-lever VAR groups, responding for the VS did not significantly differ from responding for the VS in the 2-lever SAL group. Cer- tain findings of this study support the notion that VAR has reinforcement-enhancing properties, in that the contingent VAR + VS group demonstrated a significant increase in responding for the VS, compared to saline controls. Although the noncontingent VAR + VS group failed to reach significance, active-lever responding levels were elevated. Furthermore, VAR did not demonstrate primary reinforcing properties. Interestingly, it could be that rats did not respond sufficiently for VAR in the 2-lever groups to engender a reinforcement-enhancement effect
