Proefschrift_Holstein

General introduction

2.2a Dopamine receptor agonist / antagonist In chapter 3 , I used the dopamine receptor agonist, bromocriptine to assess the role of the dopamine system, in particular the dopamine D2 receptor, in rewarded task switching. One problem with human pharmacology is that many of the pharmacological agents lack receptor specificity. Bromocriptine for example, binds primarily, but not exclusively, to the dopamine D2 receptor ( figure b and d ). However, it also acts on the dopamine D1 receptor and it can even exert its action via the noradrenaline and serotonin systems. To strengthen the claim of the involvement of dopamine D2 receptors when observing an effect of bromocriptine, a pre-treatment approach was used. To this end, bromocriptine was co-administered with sulpiride, a D2 receptor antagonist, which does not bind to dopamine D1 receptors ( figure c ).The rationale behind this design is as follows: If the effect observed after bromocriptine treatment was indeed mediated by dopamine (D2) receptor stimulation, then blocking the dopamine (D2) receptors (i.e. bymeans of co-administration of bromocriptine and sulpiride) should ‘undo’ the effect of bromocriptine. However, if the behavioural effects were mediated by another neurotransmitter system or D1 receptor stimulation, then blocking dopamine (D2) receptors should not affect the results obtained after bromocriptine treatment alone. 2.2b Methylphenidate Once dopamine has been released into the synapse, it binds to dopamine receptors, but its action is quickly terminated by reuptake, allowing it tomodulate goal-directed and reward- related behaviour on a relatively fast time scale (Floresco et al., 2003; Grace et al., 2007) ( figure a ). The dopamine transporter (DAT) is the primary mechanism for terminating the action of dopamine in the striatum. Methylphenidate (e.g. instant release: Ritalin®, slow release: Concerta®) is a drug that blocks the DAT, thereby increasing dopamine levels (Volkow et al., 2001) ( figure e ). Methylphenidate is the most commonly prescribed pharmacological treatment for ADHD. In chapter 4 , I tested patients with ADHD twice, once after intake of their normal dose of Ritalin® (or after an equivalent dose of Ritalin® for those usually taking Concerta®) and once after patients had refrained from taking their medication for 24 hours. To account for individual differences to drug responses, we took into account inter-individual variability in the DAT1 genotype. When interpreting the effects of methylphenidate it is important to keep in mind that it not only blocks the dopamine transporter, but also exerts its action by blocking noradrenaline transporters, primarily in the prefrontal cortex.

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