Effects of Ghrelin Administration on Dopamine and Effort

Will Work for Reward: Effects of Ghrelin Administration on Dopamine and Effort

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.

Study Overview

• Status: Recruiting
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: Ghrelin; Other: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Nils B Kroemer, PhD; Phone Number: +4970712982021; Email: nils.kroemer@uni-tuebingen.de
• Study Contact Backup: Name: Johannes Klaus, M.D.; Email: Johannes.Klaus@med.uni-tuebingen.de

Study Locations

• Germany
  • BW
    • Tübingen, BW, Germany, 72076
      • Recruiting
      • Department of Psychiatry & Psychotherapy, University of Tübingen
      • Contact: Andrea Heberle; Email: Andrea.Heberle@med.uni-tuebingen.de
      • Principal Investigator: Nils B Kroemer, PhD
      • Principal Investigator: Matthias Reimold, M.D.
      • Principal Investigator: Martin Walter, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ghrelin infusion; 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).	Drug: Ghrelin; Participants will receive an infusion that is intended to raise ghrelin level up to a steady plateau.
Placebo Comparator: Placebo infusion; Saline	Other: Placebo; Participants will receive a saline infusion as the placebo control condition.
No Intervention: Patients with MDD; Patients with major depressive disorder will be enrolled for comparison to healthy participants on the reward task battery, but not randomized to the ghrelin vs. saline infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ghrelin-induced changes in dopamine release	[11C]raclopride binding potential after ghrelin infusion vs. saline infusion	During the infusion (up to 90 min)
Ghrelin-induced changes in motivation	Force exerted on grip force controller to obtain rewards after ghrelin infusion vs. saline infusion	During the infusion (60-90 min after start of the infusion)
Ghrelin-induced changes in functional connectivity and perfusion	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	During the infusion (up to 90 min)
Changes (Ghrelin-induced) in hunger and satiety from baseline	Change in visual analogue scale (0-100) measures of subjective hunger and satiety after ghrelin infusion vs. saline infusion	Pre infusion and 20 minutes post infusion (compared to saline)

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University Hospital Tuebingen
• Collaborators: German Research Foundation

Study record dates

Study Major Dates

• Study Start (Actual): February 21, 2022
• Primary Completion (Anticipated): December 20, 2023
• Study Completion (Anticipated): October 31, 2024

Study Registration Dates

• First Submitted: February 22, 2022
• First Submitted That Met QC Criteria: April 7, 2022
• First Posted (Actual): April 8, 2022

Study Record Updates

• Last Update Posted (Actual): April 8, 2022
• Last Update Submitted That Met QC Criteria: April 7, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: dopamine; motivation; PET/MR; ghrelin; energy homeostasis
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: DFG KR 4555/7-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: After the publication of the key results of the study, all anonymized imaging data will be made publicly available (e.g., at openfmri.org). Behavioral data will be shared after aggregation at the trial or participant level.
• IPD Sharing Time Frame: Data will become available after an embargo period of 12 months after completion of the study.
• IPD Sharing Access Criteria: Until the data is publicly available, researchers may contact the lead PI to gain access.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No