Sex differences in the brain's dopamine signature of cigarette smoking

Abstract

Cigarette smoking is a major public health danger. Women and men smoke for different reasons and cessation treatments, such as the nicotine patch, are preferentially beneficial to men. The biological substrates of these sex differences are unknown. Earlier PET studies reported conflicting findings but were each hampered by experimental and/or analytical limitations. Our new image analysis technique, lp-ntPET (Normandin et al., 2012; Morris et al., 2013; Kim et al., 2014), has been optimized for capturing brief (lasting only minutes) and highly localized dopaminergic events in dynamic PET data. We coupled our analysis technique with high-resolution brain scanning and high-frequency motion correction to create the optimal experiment for capturing and characterizing the effects of smoking on the mesolimbic dopamine system in humans. Our main finding is that male smokers smoking in the PET scanner activate dopamine in the right ventral striatum during smoking but female smokers do not. This finding-men activating more ventrally than women-is consistent with the established notion that men smoke for the reinforcing drug effect of cigarettes whereas women smoke for other reasons, such as mood regulation and cue reactivity. lp-ntPET analysis produces a novel multidimensional endpoint: voxel-level temporal patterns of neurotransmitter release ("DA movies") in individual subjects. By examining these endpoints quantitatively, we demonstrate that the timing of dopaminergic responses to cigarette smoking differs between men and women. Men respond consistently and rapidly in the ventral striatum whereas women respond faster in a discrete subregion of the dorsal putamen.

Keywords: PET; dopamine; raclopride; reinforcement; sex differences; tobacco smoking.

Figure 1.

a, Probability of activation maps for male and female smokers. Note the striking difference in the right ventral striatum. b, The mean (and SE) number of voxels activated during smoking in the right ventral striatum for male and female smokers. A permutation test indicated that the mean sex difference in number of activated voxels in the right ventral striatum was highly significant (p = 0.01).

Figure 2.

a, A cluster of 20 voxels in the right ventral striatum identified by SPM: peak DA level in response to smoking is significantly higher in men than women. b, DA curves for the same cluster. The solid curves are the mean DA time courses for men (blue solid curve) and women (pink solid curve). Dashed curves are mean curve ± 1 SE.

Figure 3.

a, A nine voxel cluster in the right dorsal putamen identified by SPM: women responded significantly faster to smoking (shorter Rise Time) versus men. b, Illustration of the DA parameters that characterize a DA time course. c, The solid curves are the mean DA time courses for men (blue solid curve) and women (pink solid curve). Dashed curves are mean curve ± 1 SE.