PROJECT ABSTRACT Nicotine is the primary addictive constituent in tobacco. For an individual, chronic tobacco use is associated with a significant increase in heart disease and many forms of cancer. Increasingly, researchers are documenting health issues associated with vaping flavored e-juice containing nicotine. There are some important sex differences in chronic nicotine use and its health consequences. Women on average are impacted more by environmental and sociocultural factors, take less time to become nicotine dependent, make fewer attempts to quit, abstain for less time, relapse at higher rates, and benefit less from nicotine replacement therapy. Enormous gains to the individual and society would come from a more complete understanding of factors that contribute to nicotine use and misuse. Through Pavlovian conditioning processes, environmental stimuli associated with drugs such as nicotine can become powerful modulators of drug-seeking behavior. Another related and important factor in the development of chronic nicotine use is the pharmacological effects of nicotine serving as an internal (interoceptive) stimulus that enters into a conditioned association with other reinforcers (e.g., peer acceptance, alcohol, work breaks, stress relief, etc.). Thus, smokers/vapers over time develop a rich interoceptive conditioning history with the stimulus effects of nicotine. Our long-term objective is to understand how this conditioning history alters the trajectory of use and misuse in individuals and, in doing so, provide new clues on how to improve cessation programs. To this end, we recently developed an innovative new approach using rats that merges interoceptive conditioning of intravenous (IV) nicotine with its later self-administration. When IV nicotine is repeatedly paired with an appetitive reinforcer (i.e., sucrose), this conditioning history dose- and sex- dependently increases nicotine self-administration (21 to 126%)—an effect more profound in female rats.