Nicotine patch reduces striatal smoking-induced dopamine release compared to placebo patch

1566 Introduction: Tobacco smoking and combustible product-related deaths greatly exceed those from alcohol, firearms, AIDS, and all other drugs of abuse including opioids, combined.1 Although all available treatments for smoking cessation have only limited success rates,2 currently, the first line pharmacological treatment for tobacco smoking is nicotine replacement therapy (NRT), i.e. nicotine patch. NRT acts directly at the nicotinic-acetylcholine receptor on dopamine (DA) terminals to release DA in the striatum - which encodes reward and habit formation.3 To better understand treatment efficacy, we used a naturalistic experimental system combined with a kinetic model designed to characterize smoking-induced DA release, in vivo. The goals of this study were (1) to examine the strength of cigarette smoking-induced striatal DA release in tobacco smokers under nicotine patch and placebo patch conditions and, (2) to relate the spatial extent of DA release to smoking behavior-nicotine dependence. We hypothesized that (1) nicotine patch would reduce the spatial extent of DA release in the striatum compared to placebo patch, and (2) number of smoking pack years would be associated with the spatial extent of DA response in the striatum. Methods: Twenty-eight tobacco smokers (13 female) received a nicotine patch (21mg, daily) for 1-week and a placebo patch for 1-week in a randomized, counter-balanced order. Following 1-week under each condition and then overnight abstinence, smokers participated in two 90-minute [11C]raclopride PET scans and smoked a cigarette while lying in the scanner. We used lp-ntPET,4-7 a model of tracer uptake containing a time-varying term to identify highly localized DA transients in PET data on a voxel-by-voxel basis. lp-ntPET was fitted to PET TACs at each voxel in the pre-commissural striatum.8 DA responses were retained only for voxels if the inclusion of the time-varying term improved the fit. Each frame was smoothed with a 3D Gaussian filter before fitting. “Probability of activation” maps were generated, summed by condition and divided by the number of group members.9 Smoking pack years were calculated by multiplying the number of cigarette packs smoked per day by the number of years smoked. Participants were divided into low and high number of pack years groups using a median split analysis. Probability of activation maps for low pack years and high pack years were made for exploratory analysis. Results: Nicotine patch reduced the spatial extent of DA release and the probability of DA activation following cigarette smoking compared to smoking following placebo patch (Figure 1A). The high number of pack years group had higher spatial extent and probability of DA activation in the striatum during the placebo patch condition compared to the low number of pack years group (Figure 1B). Conclusions: Consistent with our hypotheses, the nicotine patch reduced the strength of cigarette-induced striatal DA response compared to placebo patch, suggesting a potential mechanism for the effect of nicotine patch treatment on the rewarding response of cigarette smoking. Number of pack years was associated with the strength of the striatal DA response in both reward-related and habit-formation hubs of the striatum. These preliminary findings suggest that pack years of tobacco smoking contribute to DA response and that our method might be able to parse out group differences in smoking behavior characteristics.