The role of dopamine and noradrenaline in probability and reward value processing.

The way humans behave is greatly affected by the principle 'expected utility'.
Expected utility is the product of subjective value of the outcome of an act
and the probability of that outcome. In our prior study (approved by the METC,
protocol number 12/238, NL39997.041.12) we observed an anteriorly localized
brain potential (the P200) that was sensitive to cues signaling reward and it
was also sensitive to cues signaling the probability of an upcoming target.
Specifically, the P200 was larger for cues signaling reward compared to cues
signaling no reward. And the P200 was also larger for cues signaling high
compared to low target probability. We also observed a more posteriorly located
brain potential (the P300) that was sensitive to cues signaling reward. This
P300 was larger for cues signaling reward compared to no reward.
The current study aims to clarify whether the brain dopamine and noradrenaline
system are involved in the processing of reward value and probability. More
specifically, we want to investigate whether these neurotransmitter systems
underlie the the brain potentials sensitive to reward and probability (the P200
and P300). We expect that the effect of reward on the posterior P300 decreases
under noradrenaline antagonism by clonidine, specifically. Moreover, we expect
that the effect of reward and probability on the anterior P200 decreases under
dopamine antagonism by haloperidol, specifically.

This study aims to clarify whether the brain dopamine and noradrenaline system
underlie the electrocortical responses (event-related potentials) that are
sensitive to cues signalling reward and probability, the P200 and P300.

The main part of the study consists of 3 medication sessions. This is a
placebo-controlled, double blind cross-over study.
EEG will be measured during each of the medication sessions.

During each of the three medication sessions 2 mg haloperidol, 150 microgram
clonidine or placebo will be administered to included individuals. The time
between sessions is at least 1 week.
During each session one of these drugs (haloperidol, clonidine or placebo) will
be administrated (in a double blind fashion).
The order of the sessions (haloperidol/placebo/clonidine) will be balanced
across participants.

We expect this study to be a moderate risk study. There is, however, a
possibility that transient side effects occur.
Mostly reported side effects for haloperidol are sedation and extrapyramidal
side-effects. Mostly reported side effects for clonidine are a dry mouth and
sedation. For a complete overview of reported side effects, see IB.
Strict measures will substantially reduce the risk of side effects to occur.
First, there are strict in/exclusion criteria (including no medication use, no
history of serious medical conditions, no low blood pressure, see protocol
section 4.2/4.3). Second, the study will be run in the hospital, where medical
care is available when needed. Finally, drug effects will be monitored (by
means of actigraph measurements, velocity scaling and the POMS questionnaire).

In our opinion the burden associated with participation is acceptable. It could
be that participants feel a bit tired, because of the medication on the one
hand and because of doing the task on the other hand. To keep the experimental
sessions as comfortable as possible, participants will pause several times
during the task. Of course, participants have the right to withdraw from the
study when they want to.
The behavioral task during which EEG will be measured takes about 1 hour.
During a large part of the study (between drug administration and drug peak
level) participants do not have to perform a task.

In our opinion it is justified to perform the experiment. First, because in our
opinion the burden associated with participation is acceptable (see above).
Second, this study will have great implications on understanding and possible
treatment of psychiatric disorders (see introduction of the protocol)