Replication of sex differences in tobacco smoking-induced dopamine responses and extension to nicotine replacement therapy

Introduction Tobacco smoking is a major public health risk, and treatment efficacy differs by sex. Previous imaging studies reported sex differences in smoking-induced striatal dopamine release, but no PET study has independently replicated these findings. We applied a novel, more sensitive modeling pipeline to examine sex differences in dopamine responses to smoking and modulation by nicotine replacement therapy in archival PET data. Methods Thirty-one smokers (13 women) underwent 90-min PET scans with [11C]raclopride. Participants smoked a cigarette mid-scan (35 min) after tracer injection both following one week of placebo patch and one week of nicotine patch in a crossover design. Voxel-wise striatal time-activity curves were analyzed using our pipeline that combined the linear parametric neurotransmitter PET (lp-ntPET) model with Bayesian parameter estimation. Endpoints included spatial extent of dopamine activation and a dopamine activation metric that integrates probability of activation and peak dopamine magnitude at every voxel. Results Under placebo, men showed greater dopamine activation in the ventral striatum (p=0.047), consistent with reward-driven smoking. Women exhibited higher spatial extent in the right dorsal caudate (p=0.028) and whole caudate (q=0.033), consistent with habit- and stress-related mechanisms. The dopamine activation difference between placebo and nicotine patch conditions was larger in men than women across the whole striatum (p=0.011), indicating sex-specific modulation by constant nicotine administration. Conclusions These findings support previously observed sex differences in striatal smoking-induced dopamine responses. Sex-specific effects of the nicotine patch may be relevant to widespread findings in the literature reporting lower efficacy of nicotine replacement therapy efficacy in women.