Current therapies for nicotine dependence have limited efficacy. As such, researchers have asserted that animal models should be developed further to more closely approximate clinical treatment conditions, with the prospect that more effective treatments will be discovered. Although nicotine self-administration models in animals have been useful in understanding the behavioral and pharmacological mechanisms of nicotine abuse, they are limited in addressing certain features of treatment interventions in nicotine-dependent humans. One clinical behavioral intervention that has been widely successful involves reinforcing abstinence with alternative reinforcers. The purpose of this proposal is to extend the preclinical methodology of alternative reinforcement to more closely approximate clinical applications of this approach using nicotine self-administration assays. Differential-reinforcement-of-other-behavior (DRO) schedules, which involve delivering reinforcers for not engaging in a target response, have been shown to reduce behaviors maintained by nondrug reinforcers in animals and successfully applied in the treatment of a wide range of behavior problems in humans. In the present proposal, DRO schedules will be used to reinforce rats for not engaging in nicotine-maintained responding (abstinence) using an alternative nondrug reinforcer. The effects of DRO contingencies will be examined under a range of self-administration assays (i.e., maintenance, acquisition, and reinstatement) to determine the spectrum of conditions under which nicotine self-administration can be reduced. Findings from the proposed studies will serve as preliminary data for an R01 grant proposal. The research plan for the ROI will include examining variables that may enhance the effectiveness of DRO contingencies and suggest more effective ways of applying alternative reinforcement in clinical interventions. In addition, given that combined pharmacological and behavioral interventions are most effective in treating nicotine abuse, another aim of the ROI proposal will be to examine the effects of combining nicotine replacement with DRO schedules of alternative reinforcement. Such studies will provide a means to evaluate the therapeutic potential of medications as adjuncts to behavioral interventions for nicotine dependence and abuse of other drugs. The proposed techniques will also provide a platform on which to examine the neuropharmacological mechanisms mediating the separate and combined effects of alternative reinforcement and pharmacological interventions on nicotine-self-administration.