Proefschrift_Holstein

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

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