Effects of ghrelin administration on dopamine and effort

• Applicants: Professor Dr. Nils Kroemer; Dr. Matthias Reimold; Professor Dr. Martin Walter
• Subject Area: Biological Psychiatry
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 457170318

Ghrelin is a stomach-derived hormone and the only known circulating peptide stimulating appetite. Animal studies have conclusively shown that ghrelin increases dopaminergic transmission and, thereby, may enhance effort. However, similar evidence on the putative role of ghrelin in humans, particularly regarding symptoms of reward deficiency (“anhedonia”), is still lacking. Here, we propose to close this crucial gap by conducting a longitudinal behavioral study (Phenotyping Study) and, in a subset of healthy participants, a pharmaco-imaging study (Neuroimaging Study). First, we will assess fasting blood levels of hormones involved in appetitive behavior such as ghrelin, leptin, and insulin during an intake visit in patients suffering from major depressive disorder (MDD) and matched healthy control participants. To characterize reward function, we will conduct a set of tasks capturing various facets of anhedonia that have been associated with dopamine transmission before. Next, to unravel the causal effect of ghrelin, we will assess the effects of intravenous administration of ghrelin on dopamine signaling using a double-blind randomized cross-over design. To this end, healthy participants, who have completed the intake visit before, will be infused with ghrelin (vs. saline) while we measure dopamine release (via [11C]-raclopride positron emission tomography, PET) and assess brain function at rest (via concurrent magnetic resonance imaging, MRI). Crucially, to track ghrelin-induced effects on willingness to work for reward, we will conduct an instrumental motivation task (IMT) inside the PET/MR scanner. To flank these mechanistic insights and pave an avenue for future treatment, we will longitudinally investigate the association of ghrelin with reward function in patients suffering from depression. Based on preclinical studies and indirect evidence from human studies, we expect ghrelin to increase dopamine release in the striatum, which will, in turn, lead to an increased willingness to work for rewards. Moreover, we expect that ghrelin-induced dopamine release will be associated with a sharper tracking of the utility to work for rewards in the mesolimbic circuit during the IMT. Lastly, we will train a classifier of ghrelin-induced dopamine release based on the concurrently employed functional MRI data. Collectively, the proposed project would provide a unique resource to test an important link between the gut and the brain in the regulation of appetitive behavior. If ghrelin were to enhance effort expenditure for rewards via dopamine signaling in humans, then restoring sensitivity to ghrelin might be a promising therapy for anhedonia. We envision that our study would provide a much-needed resource for future research on metabolic and mental disorders characterized by aberrant homeostatic signaling.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Christian Jean La Fougère