Dopaminergic mechanisms of gating working memory, learning, and motivation: A pharmaco-fMRI study

Dopamine is a catecholamine neurotransmitter that plays a central role in
flexible and self-directed thought and action: Our ability to think and make
plans about stimuli that are not physically present (working memory), to learn
from new information (reinforcement learning), and to make choices based on
prior learning and our current environment (incentive motivation), all
critically rely on dopamine. Dopamine dysregulation also plays a central role
in many disorders, including Parkinson*s Disease, schizophrenia, AHDH, and
depression. The mechanisms by which dopamine influences diverse cognitive
processes in healthy and patient populations has been theorized using
biologically-plausible computational models; however further empirical
investigation is needed.

Furthering our mechanistic understanding of the role of dopamine in these
processes is beneficial, both for refining theories and computational models of
cognition, and for providing insights that can improve treatment of
dopamine-related disorders.

The primary objective of this study is to unravel the effects of dopamine D2
receptor stimulation on gating of working memory, reinforcement learning, and
reward-based motivation, and their associated physiological changes (measured
with fMRI and eyetracking).

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. All
participants will complete one screening sessions and 2 pharmaco-fMRI sessions,
all of which will take place at the Donders Centre for Cognitive Neuroimaging.
During each pharmaco-fMRI sessions, subjects will receive an oral dose of
sulpiride or placebo, and the order of sulpiride vs. placebo will be
counterbalanced across subjects.

Participants will take part in 3 test sessions. One intake session (3 hours)
and two pharmaco-fMRI sessions (6 hours each) and will complete several
questionnaires at home (1 hour total). The intake session will involve a
medical and psychiatric screening interview, neuropsychological tests, an ECG
measure, and some training on the tasks for the pharmaco-fMRI sessions. On the
days preceding the pharmaco-fMRI sessions participants will have to adhere to
some simple restrictions with respect to medication, alcohol, and drug intake.
On the morning of each test session participants will have to refrain from
smoking and caffeinated drinks. During the pharmaco-fMRI sessions participants
will receive 400mg sulpiride or placebo, and will be asked to complete some
questionnaires and perform tasks testing learning and memory, inside and
outside of the fMRI scanner. Sulpiride can be administered safely without any
relevant risk of serious side effects and has been approved for clinical use in
the Netherlands.