ABSTRACT: Project 3. Preclinical Studies The preclinical project in the Center has the purpose of discovering new treatments which have promise for enhancing success with tobacco smoking cessation and to provide better basic understanding of the neurobehavioral processes underlying nicotine reinforcement to build a foundation for further treatment development. In the initial phase of the Center's research effort the preclinical project has provided promising new leads for medical treatments to aid smoking cessation and important neurobehavioral mechanistic information to help guide rational drug development for further progress in enhancing smoking cessation therapy. Two of our discoveries, the efficacy of the serotonin 5HT2c antagonist lorcaserin and the triple monoamine transmitter reuptake inhibitor amitifadine in significantly reducing nicotine self-administration (SA) will be advanced to human testing in the clinical project of the Center. Our project will continue this progress in the next phase of the Center's development. The rat model of nicotine SA will be used to build on our discovery of diverse treatments based on actions at nicotinic cholinergic, 5HT2c serotonergic, D1 dopaminergic, ?2 nordrenergic, H1 histaminergic and NMDA glutaminergic receptor systems will be followed up in three ways. 1) Combinations of these effective treatments will be evaluated to discover which would provide added therapeutic efficacy. 2) Differential efficacy of the diverse treatments will be tested in different subpopulations based on sex, adolescent or later age of onset of nicotine SA, low vs. high levels of nicotine SA, involvement of oral consummatory aspects of SA and pre or post cessation liability of nicotine SA. 3) The brain circuit mechanisms for the diverse treatments will be characterized through local brain area infusions of the different receptor-based treatments to see where the critical loci of actions are for the successful therapies. These studies will serve to refine the treatments for the tailored and adaptive treatment for smoking cessation in people. It has become clear that there is unlikely to be a single treatment that reaches all smokers to enable them to successfully quit. The diverse toolbox of treatments and further understanding of their mechanisms of action will help provide the clinical studies in our Center and the field in general to advance the goal of smoking cessation for the full variety of smokers.