Flavor additives in tobacco products and e-cigarettes are familiar stimuli with 'incentive' properties - they have been paired with sweet tastes or caloric post-ingestive effects in the past. These additives are intended to increase self-administration of nicotine by increasing palatability; however, they may also interact with the potent 'reward-enhancing' effects of nicotine to promote acquisition of self-administration and compulsive use. The inclusion of flavors with conditioned rewarding properties may also promote neurochemical changes that are correlated with long-term use and dependence. The specific objectives of the proposed studies are to investigate whether these flavor additives promote harm by increasing the number of individuals who smoke or use e-cigarettes; to determine whether flavor additives promote the development of nicotine dependence using pre-clinical models that measure motivation to take the drug as well as taking the drug in the face of aversive consequences; and to determine whether inclusion of flavor additives in the nicotine self-administration paradigm increases levels of mesotelencephalic dopamine, a neurochemical change that may contribute to compulsive substance use and dependence. We predict that flavors with conditioned reinforcing properties (paired with sweeteners in the past) will promote acquisition of self-administration at low nicotine doses, will increase nicotine 'dependence', and will cause regionally specific increases in neural growth factors. This research will make a significant impact on public health as it may reveal an important feature of smoked tobacco and e-cigarettes that encourage experimentation, repeated use, and dependence. The project builds on pre-clinical self-administration with the important innovations of including flavor stimuli in te self- administration paradigm and specifically using stimuli that model flavor additives in tobacco and e-cigarettes (flavors with incentive motivational properties). The experiments will begin by 'conditioning' the additives (e.g., menthol and strawberry) with incentive properties by pairing them with a sweet reward. This models most flavor additives (e.g., menthol, licorice, cocoa) which are familiar to most individuals who smoke before they are ingested in tobacco or e-cigarette formulations (e.g., candy canes, mints, ice cream, etc.). The flavor will then be self-administered in its unsweetened form, orally, by licking at a sipper tube. Nicotine is self- administered intravenously in conjunction with oral flavor delivery. This models inclusion of flavor additives in tobacco and e-cigarettes, which do not include potent sweeteners. Based on our preliminary findings, we expect that these conditioned reinforcing flavors will 1) reduce the dose of nicotine needed to acquire self- administration and 2) increase the motivation to obtain nicotine 3) increase nicotine self-administration in the face of negative consequences and 4) increase levels of dopamine in mesotelencephalic regions in which synaptic plasticity is associated with drug self-administration and substance dependence. We anticipate that these studies will have broad impact on the nicotine self-administration paradigm and public health.
Flavor additives included in all tobacco and e-cigarette products are familiar, palatable, and usually associated with rewards like sugar and calories (e.g., mint, strawberry, cherry, licorice, cocoa, etc.). Nicotine is a reward enhancer and is known to increase the rewarding effects of some flavors. The proposed studies will investigate whether taking nicotine in combination with these flavor additives promotes harm by increasing the use of tobacco and e-cigarettes and altering brain reward systems.
