Proefschrift_Broeders

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.

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