Proefschrift_Holstein

General discussion

6 , the demonstration that infusion of a dopamine antagonist in the striatum will impair performance on the rewarded task-switching paradigm will further substantiate a role for striatal dopamine in motivated cognitive control. In chapter 3 and 5 , we aimed to elucidate the role of specific dopamine receptors in motivated cognitive control. Two hypotheses should be assessed in future work. First, given previous work showing that reward-related effects of methylphenidate are blocked by a dopamine D1 antagonist, but not by dopamine D2 receptor antagonism (Meririnne et al., 2001), dopamine D1 receptor stimulation is a likely candidate for a role in motivated cognitive control. Second, a role for concurrent dopamine D1 and D2 receptor stimulation in reward motivation (Ikemoto et al., 1997) has been suggested. This suggests that concurrent D1 and D2 receptor stimulationmay also be crucial for motivated cognitive control.These hypotheses can be tested by administration of a compound which increases dopamine levels (e.g. methylphenidate), in combination with the pre-treatment approach we used in chapter 3 . More specifically, in addition to a placebo session, the administration of methylphenidate should be combined with the pre-treatment of (1) placebo, (2) a dopamine D1 receptor antagonist, (3) a dopamine D2 receptor antagonist and (4) a combination of both a D1 and D2 receptor antagonist. The administration of methylphenidate after pre-treatment with a placebo is hypothesized to improve motivated cognitive control compared with the placebo session. Pre-treatment with a dopamine D2 receptor antagonist will not have any effect on motivated cognitive control ( chapter 3 ). However, if dopamine D1 receptor stimulation mediates the effect of methylphenidate on motivated cognitive control, the effects of methylphenidate will be blocked after pre-treatment with a dopamine D1 receptor antagonist. Crucially, if motivated cognitive control is mediated by a combination of dopamine D1 and D2 receptor stimulation, only pre-treatment of both a dopamine D1 and D2 receptor antagonist will fully block the effects of methylphenidate. One problem however is the lack of an available dopamine D1 agonist or antagonist for use in research with healthy human subjects. Until a suitable pharmacological agent becomes available, the rodent paradigm presented in chapter 6 can be used to assess whether a dopamine D1 agonist (which is available for use in rodents) affects successful motivated cognitive control. In addition, methylphenidate acts not only on dopamine transporters, but it also blocks noradrenaline transporters. To confirm that dopamine mediated the effects of methylphenidate, an additional session should be included to show that the effects of methylphenidate can be blocked with co-administration of a (non- selective) dopamine receptor antagonist. In chapter 1 , we proposed that motivation can have opposite effects on cognitive stability and flexibility. Although the results in chapter 5 are generally congruous with this idea, this should be addressed formally in future experimental work. For example by using the reward Stroop paradigm presented in chapter 1 ( figure 1.3 ) to contrast the effects of cognitive widening and focusing on Stroop performance in one paradigm. Cognitive widening will be beneficial for performance on congruent Stroop targets, whereas cognitive focussing will benefit performance on incongruent trials. Future experimental work is necessary to reveal whether

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