Dopamine, Reward Learning and Sex Hormones

NCT ID: NCT06365515

Last Updated: 2024-05-09

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 90 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-05-31
• Study Completion Date: 2025-12-31

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.

Detailed Description

This study will investigate naturally cycling women (n = 60) and men (n = 30). During the intake session (C1) energy expenditure of men and women in their EF cycle phase will be assessed by indirect calorimetry, participants will perform a training EAT task, and hormones (e.g., estradiol, progesterone, testosterone, and their precursor steroids and metabolites) will be assessed from blood samples. Energy expenditure will be assessed at another time point again (C2) (women with different hormonal profiles) and blood samples will be collected.

During the neuroimaging sessions (S1, S2) both men and women will be measured, 30 women in their EF menstrual cycle phase and another 30 women in their ML phase. All participants will take part in the Effort Allocation Task, an effort-based decision-making task during an L-DOPA-based pharmaco-neuroimaging using functional magnetic resonance imaging (fMRI). To disentangle the influence of L-DOPA within a randomized double-blind design, in one session an L-DOPA-based pill (Madopar, 150mg/37.5 mg L-DOPA/ benserazide) and in another one a placebo pill will be administered. Sex steroids (e.g., progesterone, estrogen, testosterone) and metabolic hormones (e.g., glucose, insulin, triglyceride, ghrelin) will be obtained from blood samples. Before and after the MR scanning a reinforcement learning task will be examined.

Over one month, a smartphone survey will be used to regularly record mood, premenstrual symptoms, and information on food cravings. Participants will be asked to start filling out the daily survey after C1 and continue it for 30 days.

Conditions

Hormonal Changes; Menstrual Cycle

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: TRIPLE

Study Groups

Women in EF

Healthy women in the early follicular menstrual cycle phase

Group Type: EXPERIMENTAL

Levodopa administration

Intervention Type: 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.

Placebo administration

Intervention Type: DRUG

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

Women in ML

Healthy women in the mid-luteal menstrual cycle phase

Group Type: EXPERIMENTAL

Levodopa administration

Intervention Type: 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.

Placebo administration

Intervention Type: DRUG

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

Men

Healthy men

Group Type: EXPERIMENTAL

Levodopa administration

Intervention Type: 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.

Placebo administration

Intervention Type: DRUG

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

Interventions

Levodopa administration

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.

Intervention Type: DRUG

Placebo administration

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

Intervention Type: DRUG

Other Intervention Names

Madopar® tablets (Levodopa and Berazidhydrochlorid; Roche); Placebo tablets (P-Tabletten White, Lichtenstein)

Eligibility Criteria

Inclusion Criteria

• 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)

Exclusion Criteria

• 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

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

German Research Foundation

OTHER

Sponsor Role: collaborator

Uppsala University

OTHER

Sponsor Role: collaborator

University Hospital Tuebingen

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nils B Kroemer, Professor

Role: PRINCIPAL_INVESTIGATOR

Department of Psychiatry & Psychotherapy, university of Tübingen

Locations

Department of Psychiatry & Psychotherapy, University of Tübingen

Tübingen, Baden-Wurttemberg, Germany

Site Status: RECRUITING

Countries

Germany

Central Contacts

Nils B Kroemer, Professor

Role: CONTACT

nils.kroemer@uni-tuebingen.de

+4922828711151

Johannes Klaus, MD

Role: CONTACT

Johannes.Klaus@med.uni-tuebingen.de

Facility Contacts

Andrea Heberle

Role: primary

Andrea.Heberle@med.uni-tuebingen.de

Other Identifiers

TUE010_IRTG_P5

Identifier Type: -

Identifier Source: org_study_id