Smoking is a major public health problem, but the mechanisms underlying nicotine dependence are still unknown. UCI Center investigators have identified personality characteristics of high and low nicotine-dependence susceptibility (NDS), and have developed predictive models of future smoking behavior. The focus of the proposed fluorodeoxyglucose (FDG) and fluoro-L-dopa (F-Dopa) Positron Emission Tomography (PET) studies is to link differences in NDS and nicotine-related behaviors with the effects of nicotine on brain functioning. By determining the changes in brain glucose metabolism with FDG PET in response to nicotine, we hope to elucidate the neuronal systems that underlie differential susceptibility to nicotine. We hypothesize that subjects of high NDS will experience a larger brain metabolic change in the """"""""prefrontal system"""""""" (mesocortico- limbic system plus associated limbic thalamus) from nicotine challenge than low NDS subjects while performing an attentional task. We propose that the amygdala plays a key role in distinguishing subjects of high and low NDS and is activated to a greater degree in the low NDS subjects. We propose to study non-smokers and smokers with low and high NDS traits with the same nicotine challenge paradigm while performing an attentional and a provoked aggression task. We hypothesize that smoking cessation in high NDS subjects will be characterized by a greater alteration in prefrontal system activity and a corresponding decrease in F-Dopa uptake in striatum and orbital cortex than in low NDS subjects. Our PET approach is unique in its focus on individual differences in nicotine-dependence susceptibility as the key variable in understanding the rewarding effects of nicotine and the difficulties in smoking cessation.
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