Investigating the role of dopamine in healthy and pathological gambling: A pharmaco-fMRI study

Study 1:
People often avoid risks with losses even when they might earn a substantially
larger gain, indicating a differential sensitivity to gains and losses. This
behaviour, termed "loss aversion", has been associated with dopamine-rich areas
such as the ventral striatum, but causal evidence linking loss aversion and
dopamine is still missing. The first goal of this study is to use pharmaco-fMRI
in healthy subjects to provide such evidence. We will further test the
hypothesis that the risk-seeking behaviour typically observed in pathological
gamblers might reflect a reduced loss aversion resulting from a dysregulated
dopamine function.

Study 2:
Near-misses occur when an unsuccessful outcome is proximal to the designated
win. These near-misses have been shown to recruit reward-related brain areas
during gambling, raising the possibility that despite their nonwin status,
near-misses are able to enhance dopamine transmission in these areas. We will
test this hypothesis in healthy subjects, and further seek to understand
whether the persistent gambling behaviour observed in pathological gamblers
might result from a heightened sensitivity to the rewarding effect of
near-misses, in relation to a dysregulated dopaminergic transmission within the
reward circuit.

Study 1:
- Determine whether loss aversion behaviour (i.e. increased sensitivity to
losses compared to gains) is modulated by dopamine levels using a
pharmacological challenge
- Assess whether this effect is accompanied by the modulation of brain activity
in the ventral striatum using functional magnetic resonance imaging (fMRI)
- Determine whether exacerbated risk-taking observed in pathological gamblers
results from reduced loss aversion driven by abnormal ventral striatal activity
- Assess whether acute dopamine receptor blockade restore loss aversion and
ventral striatal activity to normal levels in pathological gamblers

Study 2:
- Determine whether the brain responses to wins and near-misses in a reward
task are modulated by dopamine levels using a pharmacological challenge
- Assess whether this modulation is mediated by brain activity changes in the
reward system, specifically in the ventral striatum, insula and midbrain
- Determine whether acute dopamine receptor blockade normalizes midbrain
responses to near-misses in pathological gamblers

Subjects will have to lie in an fMRI scanner and perform two
decision-making/reward tasks successively. These tasks will be performed on two
occasions: once after administration of a placebo substance and once after
administration of 400mg sulpiride. A within-subject, double-blind,
placebo-controlled, cross-over design will be employed. Behavioral and fMRI
data will be analyzed for each task following a 2 drugs (sulpiride/placebo) x 2
groups (controls/pathological gamblers) factorial design.

Each subject will receive a placebo and 400mg sulpiride on separate testing
days.

Subjects will have to lie down and stay still in an fMRI scanner while
performing two 30 min tasks involving making decisions and observing their
outcomes. These tasks will have to be performed twice: once after
administration of a placebo substance and once after administration of 400mg
sulpiride. We expect no serious adverse events following the administration of
sulpiride, since extensive previous experience has shown only rare and mild
side effects, restricted to headaches and transient drowsiness. Subjects will
further have small samples of their blood taken twice during each testing
sessions.
On the day preceding each drug session, subjects will have to adhere to some
simple restrictions with respect to medication, alcohol and drug intake. Also,
on the morning of each scanning session, subjects will also have to refrain
from smoking and stimulant containing drinks.