Neurobehavioral mechanisms linking childhood adversity to increased risk for smoking

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Adverse childhood experiences (ACEs) have been linked to increased risk of tobacco use and other substance use disorders. In particular, individuals with a higher number of ACEs are more likely to smoke cigarettes, initiate smoking at earlier ages, progress to heavier smoking, have higher levels of dependence, and are less likely to quit. However, very few human laboratory studies have been conducted to examine interactions between ACEs and risk for smoking, and the mechanisms underlying these associations are poorly understood. Based on several converging lines of evidence, we propose a translational framework in which ACEs are associated with alterations in corticostriatal circuitry contributing to dysregulated reward processing, which in turn increases sensitivity to reinforcing effects of drugs of abuse, including nicotine. The proposed research will apply a laboratory model of initial nicotine exposure using nasal spray to examine subjective reactions and reinforcing effects of nicotine among young adult non-smokers (n=150) with a history of ACEs ranging from 0 to 4 or more. Participants will first complete a functional neuroimaging protocol designed to assess mesolimbic reactivity to monetary reward, prefrontal inhibitory control, and corticostriatal functional connectivity. Subjective reactions to 0, .5, or 1 mg doses of nicotine nasal spray will be assessed during three separate fixed-dose visits. We will then evaluate reinforcing effects of nicotine during a choice session. In general, we hypothesize that increased exposure to ACEs will be associated with greater positive subjective and reinforcing effects of nicotine, that deficits in corticostriatal circuitry will mediate the association between ACEs and nicotine reactions, and that this association will be stronger among women. These results will provide a critical translation from animal models demonstrating consequences of early life stress on neurobiological pathways relevant to addiction. Moreover, this work will help to explain the increased risk for smoking among individuals exposed to ACEs and will have implications for prevention and treatment of smoking in this high-risk population and beyond.