For the current proposal, we are planning to continue with the development of a novel self-administration paradigm to examine how known precipitants of relapse (i.e., nicotine deprivation, smoking availability, and alcohol) facilitate lapse behavior for the purpose of medication screening. The first occurrence of smoking during a cessation attempt is a critical transition, as the vast majority of abstinent smokers who experience a lapse return to baseline levels of smoking. This transition represents an important target for medication development and as a result, we have decided to focus our models on early lapse behavior. To date, there has been limited work developing lapse/relapse models of smoking, and to our knowledge, only one study has examined medication effects with such a model. Building on our previous work developing innovative self-administration models to assess medication effects, we are proposing to conduct a series ofparadigrnatic studies to develop smoking lapse models that incorporate multiple factors that precipitate relapse behavior and then to assess the sensitivity of these models with medications known to affect the models' primes. The two human laboratory models that we are proposing to investigate for this project will examine the influence of multiple primes (i.e., nicotine deprivation, smoking availability, alcohol) on two primary aspects of early lapse behavior: 1) ability to resist the first cigarette and 2) subsequent smoking. The Nicotine Deprivation Model will model the influence of nicotine deprivation + smoking availability on early lapse behavior. The Alcohol Model will model the influence of alcohol + smoking availability on early lapse behavior. Study 1 will extend our pilot work developing the Alcohol Model, to examine the sensitivity of this model to a medication known to attenuate the effects of the alcohol (naltrexone). Study 2 will identify the optimal nicotine deprivation window to use in the Nicotine Deprivation Model. Study 3 will examine the sensitivity of the Nicotine Deprivation Model by investigating the ability of nicotine patch and bupropion to attenuate the ability of nicotine deprivation to prime smoking lapse behavior. Human laboratory models of smoking lapse behavior would facilitate translational work in medication development by providing an intermediary step between preclinical studies and clinical trials. Ultimately, these smoking lapse paradigms could be utilized by us and others in the scientific community to screen promising pharmacological agents.