The ability of nicotine to activate the mesolimbic dopamine pathways in the brain and the ability of nicotine to improve information processing are two mechanisms that are putatively associated with the development and maintenance of nicotine dependence. Prepulse inhibition of the startle response (PPI) is a measure that is sensitive to changes in mesolimbic dopamine activation and sensitive to changes in information processing. The first aim of the proposed studies is to test the effects of smoking high nicotine cigarettes, as compared to low nicotine cigarettes, on PPI and other psychophysiological and subjective measures. The second aim is to determine whether these effects are moderated by individual differences in nicotine dependence and sensitivity. The third aim is to determine whether these effects are related to individual differences in smoking cessation. The proposed research will test the following primary hypotheses: 1) PPI will show an overall decrease immediately after smoking each high nicotine cigarette (short interval assessment) and an overall increase at 25 minutes after smoking (long interval assessment); 2) Smokers high in nicotine sensitivity will not show a decrease in PPI at the short interval assessment after the first high nicotine cigarette but will show a decrease to the second and third high nicotine cigarettes, while smokers low in nicotine dependence and sensitivity will show a decrease after the first cigarette but no decrease to the second and third cigarettes; 3) Smokers who show the greatest cumulative decreases in PPI across the three high nicotine cigarettes will demonstrate the shortest latency to relapse after a quit attempt. Results that support the hypotheses would suggest that smoking results in mesolimbic activation at the short interval, as well as improvements in cognitive processing at the long interval, that individual differences in smoking patterns moderate the ability of nicotine to activate dopamine circuitry, and that this activation is related to outcomes. The findings' are expected to establish a readily identifiable phenotypic marker for the reinforcing effects of nicotine, to constitute a foundation for future research on the underlying genotype, and to guide the development of new interventions.

R21CA081637

1999-07-01

2002-06-30