Obesity is associated with high serotonin 4 receptor availability in the brain reward circuitry

The neurobiology underlying obesity is not fully understood. The neurotransmitter serotonin (5-HT) is established as a satiety-generating signal, but its rewarding role in feeding is less well elucidated. From animal experiments there is now evidence that the 5-HT(4) receptor (5-HT(4)R) is involved in food intake, and that pharmacological or genetic manipulation of the receptor in reward-related brain areas alters food intake. Here, we used positron emission tomography in humans to examine the association between cerebral 5-HT(4)Rs and common obesity. We found in humans a strong positive association between body mass index and the 5-HT(4)R density bilaterally in the two reward ‘hot spots’ nucleus accumbens and ventral pallidum, and additionally in the left hippocampal region and orbitofrontal cortex. These findings suggest that the 5-HT(4)R is critically involved in reward circuits that regulate people's food intake. They also suggest that pharmacological stimulation of the cerebral 5-HT(4)R may reduce reward-related overeating in humans.