Effects of Ghrelin Administration on Dopamine and Effort

Phase 1

Recruiting

• Conditions: Major Depressive Disorder
• Interventions: Drug: Ghrelin; Other: Placebo

• Registration Number: NCT05318924
• Lead Sponsor: University Hospital Tuebingen

Brief Summary

Ghrelin is a stomach-derived hormone and the only known circulating peptide that stimulates appetite. Animal studies have conclusively shown that ghrelin increases dopaminergic neurotransmission and, thereby, enhances effort. However, similar evidence on the putative role of ghrelin in humans is still lacking. Here, the investigators propose to conduct a \[11C\]-raclopride PET/MR study after intravenous administration of ghrelin vs. saline in healthy individuals. First, during an intake visit, the investigators will assess fasting blood levels of hormones involved in appetitive behavior such as ghrelin, leptin, and insulin. In addition, the investigators will conduct a set of tasks that have been associated with dopamine function (i.e., effort and reinforcement learning). Second, the investigators will assess the effects of intravenous administration of ghrelin on dopamine signaling using a double-blind randomized cross-over design. To this end, participants will be infused with ghrelin (vs. saline) while we determine dopamine release (via PET imaging) and assess cerebral blood flow and functional connectivity at rest (via concurrent MR imaging). Furthermore, the investigators will conduct an instrumental motivation task (IMT) where participants have to exert physical effort to obtain rewards. Based on preclinical studies and indirect evidence from human studies, the investigators hypothesize that ghrelin will increase dopamine release in the striatum and that this will, in turn, lead to an increase in the willingness to work for rewards. Moreover, the investigators expect that ghrelin-induced dopamine release will be associated with an elevated tracking of reward utility in the mesolimbic circuit during the IMT, which is known to be associated with response vigor. 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 the more promising therapeutic approach compared to antagonizing the ghrelin receptor.

Detailed Description

Not available

Study Timeline

• Status Verified: 2022-02
• Study Start: 2022-02-21
• Study First Submitted: 2022-02-22
• Study First Submitted QC: 2022-04-07
• Last Update Submitted: 2022-04-07
• Study First Posted: 2022-04-08
• Last Update Posted: 2022-04-08
• Primary Completion: 2023-12-20
• Study Completion: 2024-10-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

• Healthy control participants: never fulfilled the criteria of any mood or anxiety disorder (except specific phobia)
• Patients with major depressive disorder: diagnosis according to DSM-5 within 12 months before enrollment and presence of at least mild symptoms at enrollment (BDI II >= 14)

Exclusion Criteria

• lifetime history of a brain injury, schizophrenia, bipolar disorder, and a severe substance use disorder according to DSM-5
• obsessive-compulsive disorder, trauma- and stressor-related disorder, somatic symptom disorder, and eating disorder within a 12-month interval before the test day.
• Neuroimaging Study involving ghrelin infusion: contraindication for PET/MR (e.g., metal implants or prostheses, pregnancy, claustrophobia)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Ghrelin infusion	Ghrelin	To achieve approximately stable elevated ghrelin levels during the infusion procedure, the investigators will use a loading dose of 1 mcg/kg as well as an infusion rate of 0.051 mcg/kg/min in line with recent studies (Farokhnia, Grodin, Lee et al., 2017) and general recommendations (Garin, Burns, Kaul et al., 2013).
Placebo infusion	Placebo	Saline

Primary Outcome Measures

Name	Time	Method
Ghrelin-induced changes in dopamine release	During the infusion (up to 90 min)	\[11C\]raclopride binding potential after ghrelin infusion vs. saline infusion
Ghrelin-induced changes in motivation	During the infusion (60-90 min after start of the infusion)	Force exerted on grip force controller to obtain rewards after ghrelin infusion vs. saline infusion
Ghrelin-induced changes in functional connectivity and perfusion	During the infusion (up to 90 min)	Functional connectivity and perfusion of regions of the reward circuit (i.e., Nucleus Accumbens and Ventral Tegmental Area/Substantia Nigra) after ghrelin infusion vs. saline infusion
Changes (Ghrelin-induced) in hunger and satiety from baseline	Pre infusion and 20 minutes post infusion (compared to saline)	Change in visual analogue scale (0-100) measures of subjective hunger and satiety after ghrelin infusion vs. saline infusion

Secondary Outcome Measures

Name	Time	Method
Ghrelin-induced changes in mood	Pre infusion and 20 minutes post infusion (compared to saline)	Changes operationalized via visual analogue ratings (0-100) of positive and negative affect schedule mood items after ghrelin infusion vs. saline infusion

Trial Locations

Locations (1)

Department of Psychiatry & Psychotherapy, University of Tübingen; 🇩🇪 Tübingen, BW, Germany