Proefschrift_Holstein

General introduction

Dopamine receptor specific effects during motivated cognitive control Optimal cognitive control requires persistence in the face of distracting stimuli when pursuing a goal, and the ability to flexibly adapt behaviour when circumstances change. The dual-state theory provides a mechanism by which these opposing cognitive functions can act together to allow adaptive behaviour (Durstewitz and Seamans, 2008). This theory proposes that the cognitive effects of dopamine and dopaminergic drugs depend on the subtype of dopamine receptor that is activated in the prefrontal cortex (Durstewitz and Seamans, 2008). Two dopamine states are proposed to account for these opponent processes: A D1-dominated state, which is beneficial for robust online maintenance of information, and a D2-dominated state, which is associated with higher flexibility. Although this theory focussed on the prefrontal cortex, it is important to keep in mind that dopamine D2 receptors are abundantly expressed in the striatum, but that the expression of these receptors in the prefrontal cortex is low (Hurd et al., 2001). D2 receptors in the striatum might be especially important for the flexible updating of task representations, whereas prefrontal dopamine D1 receptor stimulation is beneficial when a task requires stable representations. Experimental- and computational work indeed showed that the striatum is especially important when the updating of prefrontal representations is required (Frank et al., 2001; van Schouwenburg et al., 2010). More specifically, the striatum is thought to act as a gating mechanism, which updates and stabilizes active maintenance in the prefrontal cortex. Interestingly, it was proposed that this gating mechanism is driven by (reward-related) midbrain dopamine (Cohen et al., 2002). The idea that dopamine D2 receptor stimulation plays an important role in flexible behaviour has further been evidenced by pharmacological experiments in rodents (Floresco et al., 2006b; Kellendonk et al., 2006) and humans (Mehta et al., 2004; Stelzel et al., 2010). In terms of reward processing, both dopamine D1 and D2 receptor stimulation play a role (Ikemoto et al., 1997; Koch et al., 2000; Cohen et al., 2007). However, the mechanism by which dopamine modulates motivated cognitive control so far remains elusive. In chapter 3 , I aimed to assess whether dopamine D2 receptor stimulation modulates task switching, or the interaction between reward and task switching. To this end, I analyzed the results of an experiment in which the dopamine D2 receptor agonist bromocriptine was administered and compared performance on the rewarded task-switching paradigm ( box 2.3 ) in a placebo session with performance after subjects received a dose of bromocriptine ( box 2.2a ). However, bromocriptine does not act exclusively on the dopamine D2 receptor, but also has some affinity for dopamine D1 receptors. To confirm that the effects of bromocriptine were indeed associated with dopamine D2 receptor stimulation, a pre-treatment approach was used ( box 2.2a ). Further, building on previous work (Aarts et al., 2010; Cools and D’Esposito, 2011), we took into account the genetically determined state of the dopamine system for two reasons. First, we aimed to explain inter-individual differences in responses to dopaminergic drugs and on task performance. Second, we exploited variation in the DAT1 genotype because the DAT is most abundant in the striatum. Therefore, it is conceivable that

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