Cholinergic and dopaminergic modulation of cognitive flexibility and stability

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In a constantly changing environment, individuals must be able to balance between the stabilization of task relevant representations and flexible updating of these representations in response to changing demands. The prefrontal cortex and basal ganglia are key regions to these processes. Genetic variations and pharmacological manipulations of dopaminergic neurotransmission modulate the balance between flexibility and stability. Effects of dopaminergic drugs are however small and show individual variation, which suggests that other neurotransmitters may also play a role. We previously provided evidence for a nicotinic cholinergic modulation of cognitive stability, which was modulated by individual differences in dopaminergic receptor genes. A wealth of animal data provides evidence for cholinergic-dopaminergic interactions in prefrontal cortex and basal ganglia, there is however a paucity of studies on neurotransmitter interactions in the human brain and none has investigated how cholinergic-dopaminergic interactions contribute to cognitive flexibility and stability. The current grant proposal aims to investigate with functional magnetic resonance imaging (fMRI) in healthy young volunteers how cholinergic and dopaminergic neurotransmitter systems interact in the healthy human brain to achieve this dynamic balance between cognitive stability and flexibility. We will perform three psychopharmacological experiments and manipulate cholinergic or cholinergic and dopaminergic neurotransmission with the cholinergic agonist nicotine and the amino acid L-Tyrosine, a precursor to dopamine and noradrenaline synthesis. All experiments will employ the same, previously established paradigm, which is a sustained attention task with switch and distractor trials to assess cognitive flexibility and stability respectively. The first aim of the proposal is to provide further evidence for a crucial role of nicotinic acetylcholine receptors in the balance between flexible and stable behaviour and to isolate the underlying neural mechanisms. Because variations in dopaminergic receptor genes modulate behavioural and neural effects of cholinergic nicotinic stimulation, a second aim is to test whether experimental manipulations of baseline dopaminergic function with L-Tyrosine impact behavioural and neural effects of nicotine, providing causal evidence for a cholinergic-dopaminergic interaction. A third objective is to study the role of variations in dopaminergic receptor genes which are central to cholinergic drug effects as well as variations in structural connectivity of dopaminergic brain regions. Overall, the project will provide novel human data on the role of cholinergic-dopaminergic interactions in executive function, which is also of relevance for understanding the inflexible behaviour and increased distraction and impulsivity that co-exist in many psychiatric disorders such as ADHD and schizophrenia.