Investigating dopamine synthesis capacity in (pathological) gamblers:
An explorative Positron Emission Tomography study

Question 1:
Presently, several lines of evidence point to a prominent role of brain
dopamine (DA) in pathological gambling (PG). This neurotransmitter has been
implicated in drug addiction, which shares striking similarities with PG. By
analogy, it was proposed that gambling-induced reinforcement is associated with
bursts of DA in the brain reward system. However, whether PG is characterized
by similar DA dysfunctions as drug addiction is still unclear. Therefore, our
first goal of the study is to clarify whether pathological gamblers suffer from
an abnormal baseline DA synthesis capacity, as compared to healthy controls.

Question 2:
There is evidence that pathological gamblers show enhanced sensitivity to
rewarding feedback while being less sensitive to punishing feedback. This
abnormal reward processing is thought to play a role in gambling behavior
spiraling out of control. Despite converging arguments, whether abnormal reward
and loss sensitivity in PG is a result of DA dysregulation remains elusive. To
answer this question, we will investigate potential correlations between
individual dopamine synthesis capacity levels and behavioral measures of reward
sensitivity.

Question 3:
Currently, Dr Sescousse and Prof Cools from the Donders Institute are using
pharmacological manipulations to test the causal role of DA in gambling
behavior (ABR number NL36779.091.11). Specifically, they are testing the
hypothesis that PG is characterized by a higher sensitivity to monetary gains
compared to losses when making risky decisions and that these distortions can
be toned down following acute drug-induced blockade of DA D2 receptors by
sulpiride.
Importantly, the effects of dopaminergic drugs on reward sensitivity vary
greatly between different individuals as a function of baseline levels of DA.
Therefore, combining the data obtained in the study by Dr Sescousse et al. with
PET DA baseline synthesis capacity measures will provide an invaluable piece of
information to fine-tune analyses and improve our understanding of the complex
interplay between DA, reward sensitivity and gambling.

Objective 1:
- Determine whether baseline dopamine synthesis capacity levels in the striatum
are different between pathological gamblers and healthy controls

Objective 2:
- Determine whether pathological gamblers show different reward and punishment
sensitivity compared to healthy controls.
- Assess whether basal dopamine synthesis capacity levels are related to
measures of reward and punishment sensitivity.

Objectiven 3:
- Determine whether the dopaminergic drug effects on reward and loss
sensitivity found in the study by Dr. Sescouse et al. (ABR number
NL36779.091.11) can be predicted from individual differences in baseline
dopamine synthesis capacity levels.

Subjects will visit the Radboud University on two occasions: once for an intake
session and a MRI structural brain scan, and once for the PET scan (the PET-CT
scanner is located at the department of nuclear medicine of the Radboud
University Nijmegen Medical centre).
Importantly, we aim to re-test participants included in the study currently
conducted by Dr. Sescousse et al. (project number 2011/204). This will have the
advantage of decreasing the burden on those participants, as they will not have
to come for an intake session and MRI scan (i.e. they will only come once for
the PET scan).

A group of 24 pathological gamblers will be compared to a group of 2 matched
non-gambling control participants in a between-subject design. The PET scan
session will start with completion of informed consent, after which subjects
will ingest carbidopa (150 mg) and entacapone (400 mg). A waiting period of 1h
is necessary for carbidopa and entacapone to reach maximal efficacy (delay
based on prior work and half-life, see Pharmacokinetics carbidopa and
entacapone Table). During that time, all subjects will be invited to perform a
computerized task to measure reward sensitivity.

Approximately 1 hour after carbidopa and entacapone intake, subjects will be
guided to the PET scanner where they will be invited to lie down and relax.
Patients are positioned as comfortable as possible, in a supine position, with
the head slightly fixated in a headrest to avoid movement. First a low dose CT
is made for attenuation correction (this takes 1 minute). Then a 89-minute
dynamic PET-scan will-be made of the brain. The scan starts immediately after
the bolus injection of the [18F]fluoro-dopa (F-DOPA; max 5 mCi) into an
antecubital vein. PET data acquisition will take approximately 1h30. After
completion of the PET session (approximately 2h30 in total) the subject may go
home.

Subjects will visit on two occasions: once for an intake session and a MRI
structural brain scan, and once for the PET scan. Importantly, we aim to
re-test participants included in the study currently conducted by Dr. Secousse
et al. (ABR number NL36779.091.11). This will have the advantage of decreasing
the burden on those participants, as they will not have to come for a second
intake session and MRI scan.
On the day preceding each drug session, subjects will have to adhere to some
simple restrictions with respect to medication, alcohol and drug intake (i.e.,
not take drugs and alcohol).
All subjects will be scanned 60 min after administration of an oral dose of
150mg of the peripheral decarboxylase inhibitor carbidopa and 400 mg
entacapone. Carbidopa is a decarboxylase inhibitor which prevents the
peripheral decarboxylation of [18F]fluoro-dopa (F-DOPA) and entacapone is a
catechol-O-methyl transferase (COMT) inhibitor, which is one of the metabolites
of F-DOPA, both will therefore result in greater availability of tracer to the
brain. Carbidopa and entacapone does not penetrate the blood brain barrier and
has no central nervous system effects. Furthermore, participants will have to
lie and relax in a PET scanner for 90 min while being intravenous injected with
F-DOPA. The F-DOPA will be given in tracer amounts. There are no additional
risks associated with F-DOPA because it is not pharmacologically active when
given in tracer amounts (max mSV/5 mCi). This is much lower than most
diagnostic CT protocols.