The goal of this component of the POI application is to develop methods to evaluate the relative abuse liability of tobacco products in animals. The tobacco industry is introducing several modified risk tobacco products (MRTPs) promoted to be safer or less addictive than conventional products. The Food and Drug Administration (FDA) is now required to evaluate the abuse liability of current and future MRTPs. Animal models are urgently needed for this process because they allow a) examination of critical phenomena that cannot be studied experimentally in humans (e.g., initiation of tobacco use in adolescents), b) isolation of the role of nicotine and other tobacco constituents from other factors, and c) screening of novel tobacco formulations prior to human exposure. Current animal models that only examine nicotine or other isolated constituents may not accurately assess the abuse liability of tobacco products because a) as yet unidentified compounds may contribute (positively or negatively) to tobacco abuse and b) it is the interaction of these compounds that determines the actual abuse liability of a product. The current project will address this issue by using well-established animal models to examine the abuse liability of aqueous tobacco extracts from four different MRTPs and a conventional product. These extracts provide an extensive range of nicotine and other tobacco constituents to more closely model actual product exposure in humans. Aim la will compare the reinforcing efficacy of tobacco extracts and nicotine with intravenous self-administration (SA) models using behavioral economic methods Aim 1b will compare acquisition of extract and nicotine SA in adolescent and adult rats. Aim 1c will compare extracts and nicotine in terms of their reinforcement-enhancing and aversive effects measured as changes in intracranial self-stimulation (ICSS) thresholds. Aim 2 will compare the ability of chronic infusion of extracts and nicotine to induce dependence as measured by withdrawal-induced elevations in ICSS thresholds. Because some non-nicotine constituents are known to enhance nicotine's dependence-related effects, the general working hypothesis is that tobacco extracts will have greater abuse liability than equivalent doses of pure nicotine. We also hypothesize that the proposed methods will be sufficiently sensitive to distinguish between extracts of different products. The proposed studies were specifically designed to parallel the human studies in this POI by a) employing behavioral economic methods to assess reinforcing efficacy, b) measuring withdrawal severity, and c) examining some of the same products. As such, this POI will allow validation of behavioral economics as a framework for integrating findings across species and predicting population-level abuse of different products. Examining abuse liability in adolescents will provide a critical extension of the human projects. By studying several more products than the human studies, findings in animals may help prioritize other products that need to be evaluated in humans. This study will provide the basis for standardized animal models of abuse liability to evaluate tobacco products and inform FDA regulation of performance standards.