166 / 218
164
Chapter 8
al., 2004; Floresco et al., 2006b; Durstewitz and Seamans, 2008; Stelzel et al., 2010), and was
further strengthened by the observation that pre-treatment with a dopamine D2 receptor
antagonist blocked these effects. Crucially, these effects depended on individual differences
in dopamine signalling, as measured with the
DAT1
genotype: Bromocriptine only improved
task-switching behaviour in subjects homozygous for the 10R allele and did not change task-
switching behaviour in those carrying the 9R allele. Together with the knowledge that the
dopamine transporter is most abundant in the striatum (
chapter 2
), these results suggest that
the stimulation of dopamine D2 receptors
in the striatum
is important for flexible cognitive
control. In addition, these results highlight the importance of taking into account inter-
individual differences in dopamine signalling when assessing drug effects (see
chapter 2
and
(Cools and D’Esposito, 2011). However, genetic associations do not imply causality and a
causal role for dopamine could thus not be provided. Also, when interpreting these results
it is important to keep in mind that expression of the dopamine transporter is not exclusive
to the striatum: The dopamine transporter is also abundantly expressed in the pallidum and
midbrain (Ciliax et al., 1999; Dahlin et al., 2007). In addition, some dopamine transporter
expression is present in the diencephalon, mesencephalon, hippocampus, amygdala and
cortex (Ciliax et al., 1999; Dahlin et al., 2007).
In sum, the results in
chapter 3
replicated previous work suggesting a role for striatal
dopamine in the integration between reward and cognitive control (Aarts et al., 2010).
However, the evidence in
chapter 3
did not support a role for dopamine D2 receptors in
motivated cognitive control. Moreover, the evidence for the involvement of
striatal
dopamine
(i.e. by means of
DAT1
-dependency of the results) is not indisputable. Combining genetics
with neuroimaging (e.g. functional MRI:
box 2.4
and
chapter 4
) can strengthen the evidence
for the involvement of striatal dopamine in motivated cognitive control.
Previous work has suggested a role for dopamine D1 receptor stimulation (Meririnne et al.,
2001), or both dopamine D1 and D2 receptor stimulation (Ikemoto et al., 1997; Koch et al.,
2000) in reward motivation. Methylphenidate (
box 2.2b
) is a drug which blocks the dopamine
transporter, thereby increasing dopamine levels. In
chapter 4
, we manipulated the dopamine
system by using methylphenidate, which is commonly used to pharmacologically treat
ADHD. We assessed patients with ADHD both after intake of their normal dose of Ritalin®
(or an equivalent dose for those usually taking Concerta®;
box 2.2b
) and after refraining from
methylphenidate intake for at least 24 hours. We compared these patients to a healthy control
group to assess cognitive task-related processing as a function of reward-related signalling in
the striatum of adults with ADHD. In this study, we observed that patients with ADHD after
withdrawal from their medication, compared with adults without ADHD, showed increased
neural signalling in the striatum (i.e. in the caudate nucleus) during the integration of reward
and cognitive control. As was the case in
chapter 3
, the effects in
chapter 4
also depended
on natural variation in the
DAT1
genotype: Only the subset of patients carrying the 9R allele
showed this increased striatal activation. Manipulation of the dopamine system, by treatment
of these patients with methylphenidate, normalized this increased striatal signal in the group