Proefschrift_Holstein

Chapter 8

previous work has revealed that dopamine-dependent connections between the ventral and dorsal striatum are crucial for the development of cocaine-seeking habitual behaviour ( chapter 1 and (Belin and Everitt, 2008). Overall, the work in this thesis contributes to a better understanding of the role of dopamine in the cortico-striatal-nigral circuitry, thereby contributing to our understanding of the underlying neuropathology in at least aging, ADHD, schizophrenia, addiction and OCD. The work in this thesis contributes to our general understanding of how reward motivation can alter cognitive control. The results suggest that reward motivation can have dissociable effects in subjects with different genetic predispositions, both in healthy subjects ( chapter 3 ) and in patients with ADHD ( chapter 4 ). These findings once more emphasize the importance of taking into account differences in the baseline state of the (dopamine) system when assessing the effect of dopaminergic drug. In addition, the results in patients with ADHD highlight the heterogeneity of the disorder: The effects of reward motivation on cognitive signalling in the striatum were only revealed in a subset of patients. If the inter-individual variation in the DAT1 genotype was not taken into account, the aberrant striatal processing would not have been revealed. Additional work is needed to assess whether taking into account inter-individual differences in dopamine signalling can predict individual responses to methylphenidate treatment in ADHD. Knowing exactly which neural mechanisms -including which receptor subtype- underlie changes in motivated cognitive control may be an important step forward in treating patients with ADHD and potentially also schizophrenia and OCD. Limitations Although the work in this thesis generally contributed to our understanding of the role of the striatum and dopamine in motivated cognitive control, the experiments in this thesis were not without limitations and these should be mentioned. In chapter 4 we assessed the effects of methylphenidate on motivated cognitive control in patients with ADHD. A number of limitations with respect to the effects of methylphenidate are worth mentioning. First, the effects in chapter 4 were especially evident when comparing the ADHD group to the healthy control group, but they were less conclusive when directly comparing the effects ofmethylphenidatewithin theADHDpatients (medicated vs. withdrawn from methylphenidate). Second, we cannot exclude entirely the possibility that the effects of methylphenidate in chapter 4 were due to noradrenaline, rather than dopamine ( chapter 2 ). This explanation is quite unlikely, given the observation of DAT1 –dependent effects in the striatum in chapter 4 , but firm conclusions can only be drawn after the observation that the effects of methylphenidate can be blocked with co-administration of a (non-selective) dopamine receptor antagonist ( see chapter 3 and box 2.2 ) ( future research ). Third, it is important to keep in mind that the effects of methylphenidate were assessed in patients with

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