Proefschrift_Holstein

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

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