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General introduction
In the overview in
chapter 1
, a number of hypotheses related to the role of dopamine in
motivated cognitive control were proposed. The experiments presented in this thesis aim to
address a number of these hypotheses, thereby focusing on the effects of reward motivation on
flexible switching between well-established task sets. First, the experiments presented in this
thesis speak to a causal role for dopamine in motivated cognitive control and aim to elucidate
which dopamine receptor type is involved in this process. In doing so, natural variation in
baseline dopamine signalling is taken into account to explain individual differences in task-
and drug effects. Second, following previous neuroimaging work that suggests a role for the
striatum in mediating the effect of motivation on task switching, the work in this thesis aims
to assess the necessity of the striatum. Finally, it aims to test the hypothesis that the prefrontal
cortex can alter processing in the striatum during motivated cognitive control.
Genetic differences in dopaminergic drug-response
Chapters 3 and 4
aim to further elucidate the role of dopamine and specific dopamine
receptors in motivated cognitive control by assessing the effect of dopaminergic drugs on
the integration of motivation and flexible control, both in healthy subjects (
chapter 3
) and
patients with ADHD (
chapter 4
).
One challenge with pharmacological studies is that individuals can vary greatly in their
response to drugs. This idea is illustrated by a study in which the effect of a dopamine receptor
agonist on cognitive functioning was assessed (Kimberg et al., 1997). This work revealed
that subjects with low basal memory capacity benefited from bromocriptine (
box 2.2a
) on
a range of complex cognitive tasks, whereas already high functioning individuals (with high
basal memory capacity) showed detrimental effects of the same drug
(
Kimberg et al., 1997
)
.
This phenomenon can be explained by an inverted U shaped theory, which states that an
individual’s response to dopaminergic drugs depends on the baseline state of that subject
(Cools and Robbins, 2004). Thus, dopamine can have beneficial effects on cognitive functions,
but both too low and too high levels of dopamine can impair cognitive functioning (Williams
and Goldman-Rakic, 1995; Arnsten, 1998).
One source of individual variation in basal levels of dopamine activity may arise from genetic
variation. Numerous pharmacogenetic studies have shown that individual differences in
dopamine genes can account for individual differences in response to drugs. For example,
Mattay and colleagues (2003) exploited inter-individual differences in natural variation in the
gene coding for the catechol-
O
-methyltransferase (COMT) enzyme. COMT is the primary
mechanism for terminating the action of dopamine in the prefrontal cortex. Variation in this
gene is associated with individual differences in dopamine signalling. Mattay and colleagues
showed that individuals with genetically determined low dopamine signalling performed
worse on a ‘prefrontal’ cognitive task than those carrying the allele associated with higher
dopamine signalling. However, after the administration of amphetamine, which increases
dopamine levels, performance of low baseline subjects improved, while amphetamine had