From stomach to striatum: Ghrelin infusions increase work for rewards

Preclinical evidence demonstrates that gut signals influence motivated behavior through the dopaminergic system. However, translational research in humans is scarce, and it is not known if surges of the stomach-derived hormone ghrelin acutely boost motivation via dopamine transmission. To close this gap, we investigated the effects of acyl ghrelin infusions (vs. saline) on instrumental work for rewards, brain responses, and dopamine transmission in healthy adults in a double-blind, randomized and placebo-controlled crossover study with [ 11 C]raclopride PET-fMRI. In line with preclinical findings, ghrelin enhanced hunger sensations ( p = .007), and effort for food and small rewards. Crucially, ghrelin enhanced functional connectivity between the hypothalamus and the striatum (NAcc: p SVC = .016), as well as within the striatum (NAcc<>Putamen: p SVC = .001), pointing to an enhanced coupling between homeostatic and motivational circuits. However, ghrelin did not alter dopamine binding potential (reflecting changes in endogenous tone), but boosted task-free phasic pulses of the NAcc BOLD signal ( p = .020), which were negatively associated with binding potential ( p = .034). During the task, ghrelin increased cue- (precentral gyrus: p FWE = .003) and effort-evoked brain responses (e.g., VTA/SN: p svc = .002) in accordance with increases in motivation. Together, these findings recapitulate preclinical work that ghrelin primarily boosts phasic dopamine release, reflecting enhanced incentive salience of food and smaller rewards. This highlights the potential of targeting gut-brain interactions to improve motivational symptoms, such as loss of appetite or anhedonia. Graphical Abstract