Nicotine enhances modulation of food-cue reactivity by leptin and ghrelin in the ventromedial prefrontal cortex.

Endocrine signals such as ghrelin and leptin are known to modulate the mesocorticolimbic dopaminergic system and, consequently, show associations with food and drug reward. In animal models, nicotine was demonstrated to reduce body weight by attenuating food intake and effects of leptin and ghrelin are partly modulated by nicotinic acetylcholine receptors which hint at potential interactions. However, the neuropharmacological modulation of endocrine signals by nicotine in healthy humans remains to be tested experimentally. We used functional magnetic resonance imaging to investigate food-cue reactivity after an overnight fast and following a caloric load (oral glucose tolerance test, OGTT) in 26 healthy normal-weight never-smokers. Moreover, we administered either nicotine (2 mg) or placebo gums using a randomized cross-over design and assessed blood plasma levels of ghrelin and leptin. During fasting, nicotine administration decreased correlations with ghrelin levels in the mesocorticolimbic system whereas correlations with leptin were increased. After the OGTT, nicotine increased the modulatory effects of ghrelin and leptin on food-cue reactivity, particularly in the ventromedial prefrontal cortex (vmPFC) and the amygdala. Critically, this led to an indirect modulation of the behavioral 'appetizer effect' (i.e. cue-induced increases in subjective appetite) by homeostatic feedback signals via food-cue reactivity in vmPFC. We conclude that nicotine enhances the effect of ghrelin and leptin in the valuation and relevance network which might, in turn, reduce appetite. This highlights that amplifying the impact of homeostatic signals such as ghrelin and leptin in normal-weight individuals might hint at a mechanism contributing to nicotine's anorexic potential.

Balancing reward and work: anticipatory brain activation in NAcc and VTA predict effort differentially.

Complex decision-making involves anticipation of future rewards to bias effort for obtaining it. Using fMRI, we investigated 50 participants employing an instrumental-motivation task that cued reinforcement levels before the onset of the motor-response phase. We extracted timecourses from regions of interest (ROI) in the mesocorticolimbic system and used a three-level hierarchical model to separate anticipatory brain responses predicting value and subsequent effort on a trial-by-trial basis. Whereas all ROIs scaled positively with value, higher effort was predicted by higher anticipatory activation in nucleus accumbens (NAcc) but lower activation in ventral tegmental area/substantia nigra (VTA/SN). Moreover, anticipatory activation in the dorsal striatum predicted average effort whereas higher activation in the amygdala predicted above-average effort. Thus, anticipatory activation entails the appetitive drive towards reinforcement that requires effort in order to be obtained. Our results support the role of NAcc as the main hub supported by the salience network operating on a trial-by-trial basis, while the dorsal striatum incorporates habitual responding.