Dopamine and Cognition

Rationale: To unravel the role of dopamine in gating of working memory, motivation and learning.

Objective: The primary objective of this study is to isolate effects of blocking D2 receptor stimulation on gating of working memory, reinforcement learning and reward-based motivation, and their associated physiological changes (measured with fMRI and eye tracking). The secondary objective is to assess the degree to which the effects of D2 receptor action vary as a function of proxy measures of baseline dopamine levels.

Study design: A double-blind placebo controlled within-subject design will be employed, in which young healthy participants are tested twice, once on placebo, and once on a low oral dose (400mg) of the D2 receptor antagonist sulpiride. This design and drug dose is commonly used in our lab without side effects (previously approved CMO protocols 2011/204, 2008/078 \& 2016/2646).

Study population: Healthy human participants, 18 - 45 yr old. We will recruit 46 participants.

Intervention: Participants will receive both 400 mg sulpiride and placebo, in separate sessions in a counterbalanced order.

Main study parameters/endpoints: BOLD signal measured with fMRI, and behavioural performance on cognitive tasks.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Participants will attend 3 study sessions: A screening session and 2 pharmaco-fMRI sessions (sulpiride and placebo). Participants will complete a baseline battery of tasks and questionnaires, a structural MRI scan, as well as a battery of tasks both in and outside the scanner. On the day preceding each pharmaco-fMRI session, participants will have to adhere to some simple restrictions with respect to medication, alcohol and drug intake. On the day of testing participants will have to refrain from smoking and stimulant-containing drinks. Sulpiride can be administered safely without any relevant risk of serious adverse events and has been approved for clinical use in the Netherlands.

A more detailed description can be found in the approved research protocol as well as the pre-registrations. The links to the pre-registrations will be made available upon publication.

Eligibility Criteria:
Inclusion Criteria:

* Healthy volunteers between 18 and 45 years of age
* Predominant right-handedness

Exclusion Criteria:

* Presence of prolactin-dependent tumors (e.g., pituitary prolactinoma or breast cancer)
* (History of) autonomic failure (e.g., vasovagal reflex syncope).
* (History of) clinically significant hepatic, cardiac, obstructive respiratory, renal, cerebrovascular, cardiovascular, metabolic, ocular or pulmonary disease/disorders
* (History of) epilepsy in adulthood (i.e. no insult after 18 years of age, no current medication for epilepsy and no insult in the last five years)
* Diagnosis (or history of) endocrine treatment
* Diagnosis (or history of) neuroendocrine treatment (e.g., phechromocytoma, hyperthyroidism, Cushing's syndrome)
* (History of) melanoma
* Hypersensitivity to sulpiride
* One first degree or two or more second degree family members with a history of sudden death or ventricular arrhythmia
* Abnormal QT interval (assessed via ECG)
* Uncontrolled hypertension, defined as diastolic blood pressure at rest \> 95 mmHg or systolic blood pressure at rest \> 180 mmHg
* Hypotension, defined as diastolic blood pressure \< 50 mm Hg or systolic \< 95 mm Hg
* or resting pulse rate \< 45 beats/min
* Diabetes
* History of prescribed medication within the last month prior to the start of the study.
* History of 'over the counter' medication within the last two months (with exception of occasional use of paracetamol, acetylsalicylic acid, and ibuprofen).
* Possible pregnancy or breastfeeding
* No appropriate contraception
* Undiagnosed skin lesions
* Lactose intolerance
* Glaucoma or increased risk for glaucoma
* Possible pregnancy or breastfeeding
* Metal objects in or around the body (braces, pacemaker, metal fragments, hearing devices)
* Claustrophobia
* Diagnosis (or history of) psychiatric treatment (e.g., severe depression, anorexia nervosa, severe mood disorders, mania, schizophrenia or borderline personality disorder)
* Diagnosis (or history of) neurological treatment
* (History of) drug dependence (opiate, LSD, (meth)amphetamine, cocaine, solvents, or barbiturate) or alcohol dependence
* Suicidality
* Use of MAO inhibitor, anaesthetic, antidepressant or antipsychotic drugs within the week prior to the start of the study.
* Average use of psychotropic medication or recreational drugs weekly or more.
* Cannabis use within 2 weeks prior to the start of the study, and periods of more than 3 months using weekly or more in the last 6 months
* Use of psychotropic medication, or of recreational drugs over a period of 72 hours
* prior to the test sessions, and use of alcohol within the last 24 hours before each measurement.
* Average use of more than 3 alcohol beverages daily.
* Average use of psychotropic medication or recreational drugs weekly or more.
* Habitual smoking, i.e., more than a pack of cigarettes per week and/or a self-reported inability or unease to cease smoking for 24 hours to testing.
* Regular use of corticosteroids.
* Abnormal hearing or (uncorrected) vision.
* First degree family member with schizophrenia or bipolar disorder
* Irregular sleep/wake rhythm (e.g., regular nightshifts or cross timezone travel).
* Left handedness (because lateralisations of brain activation may differ from right-handed people).