Dopamine, Reward Learning and Sex Hormones

NCT06365515 | Unknown

• 1 other identifier: TUE010_IRTG_P5
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

Hormonal transition periods during the menstrual cycle may predispose women to mental disorders. Hormonal fluctuations provide specific neuroendocrine conditions that modulate brain structure and function and these actions affect cognitive and emotional behaviors and affect energy and mood homeostasis. It is thought that these changes are driven by altered dopamine transmission. Here, the investigators aim to examine (1) how sex hormones and dopamine are linked and also (2) how hormonal changes affect motivation, mood, and energy homeostasis. To this end, dopamine intervention will be tested on effort-based decision-making and motivational circuits in three hormonal stages (i.e., women in early-follicular phase (EF), women in mid-luteal phase (ML), and men). Additionally, the effects of hormonal status on metabolic indices will be tested, and its effects on mood fluctuations in a period of a month. The investigator hypothesizes that women in EF cycle phase (1) have naturally less dopamine and show less effort, and (2) they show greater improvement in effort-based decision-making after Levodopa administration. The investigator has exploratory outcomes about (3) sex differences in reward-learning with and without Levodopa administration and explores if these differences correlate with elevated female sex hormone levels. Moreover, it is hypothesized that (4) hormonal fluctuations affect energy homeostasis, thus women in their EF cycle phase have higher energy expenditure and (5) they report more negative mood than in their mid-luteal (ML) cycle phase.

Conditions

Hormonal Changes; Menstrual Cycle

Keywords

dopamine; fMRI; energy homeostasis; mood homeostasis; sex hormones; motivation; menstrual cycle

Outcome Measures

Primary Outcomes (4)

• Motivation to work for rewards: force of pressing grip force device (GFD) to gain food and monetary rewards circuitry during effort-based decision-making

  Operationalized via the relative force exerted on GFD in an effort allocation task during either the first seconds of each trial (invigoration) or each complete trial (maintenance). Levodopa compared to placebo condition. Outcomes will be compared between groups and will be associated with blood hormone levels.

  During Effort Allocation Task (30 minutes) 45-75 minutes after pharmacological challenge

• Reward-related brain responses in the reward network during effort-based decision-making

  Comparing brain activity (BOLD signals) in response to feedback in regions of the reward network (ROIs: Nucleus Accumbens (NAcc), Putamen, Caudate, Ventral Tegmental Area (VTA), Amygdala, Prefrontal Cortex (PFC), Orbitofrontal cortex (OFC), Anterior Cingulate Cortex (ACC), Insula). Levodopa compared to placebo condition. Outcomes will be compared between groups and will be associated with blood hormone levels.

  During task-based neuroimaging (45-75 minutes after drug administration)

• Reward anticipation on a neural level

  Comparing brain activity (BOLD signals) in reward-related brain regions (ROIs: NAcc, striatum, PFC, ACC) during the presentation of reward cues with high vs. low reward magnitude after Levodopa administration vs. placebo. Outcomes will be compared between groups and will be associated with blood hormone levels.

  During task-based neuroimaging (45-75 minutes after drug administration)

• Execution of effort on a neural level

  Comparing brain activity (BOLD signals) in reward-related brain regions (ROIs: Striatum, Insula, ACC, PFC) during force exerted on GFD in an effort allocation task after Levodopa administration vs. placebo. Outcomes will be compared between groups and will be associated with blood hormone levels.

  During task-based neuroimaging (45-75 minutes after drug administration)

Secondary Outcomes (5)

• Resting-state functional connectivity

  During resting-state neuroimaging (10 minutes)

• Changes in reinforcement learning

  During value-based decision-making task (15 minutes) measured 15 minutes before Levodopa administration and 90 min after

• Menstrual cycle induced changes in mood and food cravings

  Measured every day (5 minutes) over the period of one month

• Changes in resting energy expenditure

  Measured twice 1-2 weeks apart, measurement takes 30 minutes

• Changes in metabolic hormone levels during the menstrual cycle

  Measured 4 times (5 minutes/day) during a period of 30 days

Study Arms (3)

Women in EF

EXPERIMENTAL

Healthy women in the early follicular menstrual cycle phase

Drug: Levodopa administration; Drug: Placebo administration

Women in ML

EXPERIMENTAL

Healthy women in the mid-luteal menstrual cycle phase

Drug: Levodopa administration; Drug: Placebo administration

Men

EXPERIMENTAL

Healthy men

Drug: Levodopa administration; Drug: Placebo administration

Interventions

Levodopa administration DRUG

To boost dopamine levels 150mg/37.5 mg L-DOPA/benserazide will be administered in line with recent studies (Kroemer et al., 2019). Maximum plasma concentration of Madopar occur \~60 minutes after drug administration. Participants will start the Effort Allocation Task 45 minutes after Levodopa administration.

Also known as: Madopar® tablets (Levodopa and Berazidhydrochlorid; Roche)

Men; Women in EF; Women in ML

Placebo administration DRUG

Placebo tablets will be administered as the placebo-controlled condition.

Also known as: Placebo tablets (P-Tabletten White, Lichtenstein)

Men; Women in EF; Women in ML

Eligibility Criteria

• Age: 20 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Naturally cycling healthy women and men
• Age between 20-35
• Body-mass index (BMI): 18-28 kg/m2
• German or English language fluency
• Normal or corrected to normal vision
• For women: Regular menstrual cycle, no hormonal contraception (between 25 and 31 days)

You may not qualify if:

• Lifetime history of brain injury, stroke, epilepsy, seizures, schizophrenia, bipolar disorders, or severe alcohol/substance dependence, premenstrual dysphoric disorder (anamnestic survey)
• Mood disorder, anxiety disorder, obsessive-compulsive disorder, trauma- and stressor related disorder, somatic symptom disorder or eating disorder in the last 12 months prior to testing (anamnestic survey)
• Severe/uncontrolled medical problems such as hormonal, metabolic, heart or chronic diseases (e.g., severe hypertension, diabetes, dysfunctions of the thyroid, or congestive heart failure)
• Pregnancy, delivery, and lactation (current and within the last year; anamnestic survey)
• Undergoing regular hormonal treatment
• Daily smoking (nicotine, shisha, e-cigarettes) or \>1/week (cannabis)
• History of malignant melanoma, angle-closure glaucoma, gastrointestinal ulcers, and osteomalacia
• Hypersensitivity to: Microcrystalline cellulose, Mannitol (Ph.Eur.), Calcium hydrogen phosphate, Pregelatinized Starch (Corn), Crospovidone, Ethylcellulose, Fumed silica, Docusate sodium, Magnesium Stearate (Ph.Eur.), Iron/Ferric oxide (E 172)
• Taking certain types of medication (antihypertensive drugs, sympathomimetics, antipsychotics, drugs affecting the extrapyramidal motor system), non-selective MAO inhibitors or a combination of MAO-A and MAO-B inhibitors
• Since we will only include healthy participants, other medications that might contraindicate Levodopa (e.g., for mental disorders) will be excluded as well. Any other occasional medication will be evaluated on a case-by-case basis.
• Pathological hearing or increased sensitivity to loud noises
• Contraindication for MRI
• Claustrophobia
• Non-removable metal objects on or in the body
• Moderate or severe head injury

Sponsors & Collaborators

• University Hospital Tuebingen: lead
• German Research Foundation: collaborator
• Uppsala University: collaborator

Study Sites (1)

Department of Psychiatry & Psychotherapy, University of Tübingen

Tübingen, Baden-Wurttemberg, 72076, Germany

RECRUITING

MeSH Terms

Interventions

benserazide, levodopa drug combination; Levodopa

Intervention Hierarchy (Ancestors)

Dihydroxyphenylalanine; Catecholamines; Amines; Organic Chemicals; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Tyrosine

Study Officials

• Nils B Kroemer, Professor

  Department of Psychiatry & Psychotherapy, university of Tübingen

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Nils B Kroemer, Professor

CONTACT

+4922828711151; nils.kroemer@uni-tuebingen.de

Johannes Klaus, MD

CONTACT

Johannes.Klaus@med.uni-tuebingen.de

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Neither participants nor investigators will know at which time point the participant will receive Levodopa and placebo tablets. The tablets will be prepared by independent members of the university hospital.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The investigators will assess the effects of Levodopa administration on reward-learning using a double-blind randomized cross-over design. In a within-subject design, participants will get both conditions (Levodopa/placebo) at different time points (a few days apart). After drug/placebo administration we will assess cerebral blood flow and functional connectivity at rest (via functional MR imaging) during effort-based decision making task.

Study Record Dates

• First Submitted: April 9, 2024
• First Posted: April 15, 2024
• Study Start: May 1, 2024
• Primary Completion: December 1, 2025
• Study Completion: December 1, 2025
• Last Updated: May 9, 2024

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
• Time Frame: Data will become available after an embargo period of 12 months after completion of the study.
• Access Criteria: Until the data is publicly available, researchers may contact the lead PI to gain access.

Locations

DE (1)