Chronic smoking is a national public health problem. Associative-based interventions (cue-exposure therapy) can be effective at reducing smoking and decreasing relapse rates, indicating that acquired associations with nicotine contribute to chronic smoking and relapse. The long-term goal of this research program is to elucidate these associative processes and their role in chronic nicotine use. Pavlovian conditioned associations between a conditioned stimulus (CS) and an unconditioned stimulus (US) is one such process. In contrast to research treating nicotine as a US, little work has explored the possibility that the pharmacological effects of nicotine might serve as a CS and acquire additional excitatory properties. The present application will eliminate this deficit using a rat model. In this model, nicotine (CS) is reliably paired with the appetitive effects of sucrose (US). An association is evidenced when nicotine differentially evokes anticipatory food-seeking behavior. Specific Aim 1 will test whether changing the nature of the nicotine CS alters development or expression of conditioned responding; alterations include changes in nicotine dose and time between nicotine administration and testing. Aim 2 will test whether an associative learning or a state-dependent learning process is responsible for differential control of food seeking by nicotine. Aim 3 will assess the ability of several ligands (ABT-418, bupropion, nornicotine, cytisine, epibatidine) to prompt nicotine-like conditioned responding (stimulus substitution). Differential substitution patterns will provide insight into the neurobiological processes mediating the CS effects of nicotine. Aim 4 will assess whether extinction with a ligand that shares stimulus properties with nicotine will lead to the development of a competing association that transfers to a nicotine CS. This transfer of extinction (associative substitution) would be evidenced if rats trained with a nicotine CS, but receive extinction with another drug, show loss of conditioned responding when retested with the unextinguished nicotine CS.