Elsevier

Biological Psychiatry

Volume 69, Issue 12, 15 June 2011, Pages e113-e125
Biological Psychiatry

Review
Inverted-U–Shaped Dopamine Actions on Human Working Memory and Cognitive Control

https://doi.org/10.1016/j.biopsych.2011.03.028Get rights and content

Brain dopamine (DA) has long been implicated in cognitive control processes, including working memory. However, the precise role of DA in cognition is not well-understood, partly because there is large variability in the response to dopaminergic drugs both across different behaviors and across different individuals. We review evidence from a series of studies with experimental animals, healthy humans, and patients with Parkinson's disease, which highlight two important factors that contribute to this large variability. First, the existence of an optimum DA level for cognitive function implicates the need to take into account baseline levels of DA when isolating the effects of DA. Second, cognitive control is a multifactorial phenomenon, requiring a dynamic balance between cognitive stability and cognitive flexibility. These distinct components might implicate the prefrontal cortex and the striatum, respectively. Manipulating DA will thus have paradoxical consequences for distinct cognitive control processes, depending on distinct basal or optimal levels of DA in different brain regions.

Section snippets

Individual Differences in DA Action

Findings from psychopharmacological studies with human volunteers indicate that the effects of dopaminergic drug administration depend on baseline levels of performance (29, 32, 38, 39, 40, 41). For example, we first observed in 1997 that the effects of bromocriptine on PFC function are not the same for all subjects but interact with the baseline working memory abilities of the subject (29). The drug improved cognition in subjects with lower baseline working memory abilities in the “undrugged”

Variability in Basal DA Levels in the PFC of Nonhuman Animals

What might be the origin of these performance-dependent effects of dopaminergic drug administration? Accumulating evidence from research with mice, rats, and monkeys indicates that it likely reflects variability in baseline levels of DA, specifically in the PFC (51, 52, 53, 54, 55). For instance, Phillips et al. (56) have shown in rats that poor performance on a difficult (working) memory task (with a long delay) was accompanied by low DA levels in the PFC, whereas good performance on an easy

Baseline-Dependent Mechanisms of DA Action in Humans

So far we have seen that dopaminergic drug effects in nonhuman animals vary as a function of baseline levels of DA in the PFC. Is there evidence for similar baseline dependency of dopaminergic drug effects in humans? One source of such evidence comes from studies of drug effects that take into account genetic differences between individuals (see for review [72]).

One of the best-studied polymorphisms is the Val158 Met polymorphism in the catechol-O-methyltransferase (COMT) gene. Catechol-O

Distinct Roles for Striatal and PFC DA

Traditionally, cognitive effects of DA are ascribed to modulation of the PFC. However, recent theories as well as empiric data have highlighted a complementary role for DA in the striatum in working memory and cognitive control (101, 102, 103, 104, 105, 106). Critically, studies in animals investigating the role of D1 receptors in the PFC have most commonly focused on the delay period of delayed response tasks, which requires the stabilization of an earlier presented stimulus across a short

PD Studies Strengthen the Link Between DA and Cognition

A different approach toward assessing the influence of DA on cognitive function in humans is by testing patients with PD. Parkinson's disease is a progressive, neurodegenerative movement disorder and characterized by a spatiotemporal progression of nigrostriatal and mesocortical DA depletion. In addition to deficits in motor control, PD is also accompanied by significant cognitive impairments even in the early stages of the disease. Central nervous system levels of DA can be manipulated over

Summary

In summary, DA plays a critical role in cognitive control, which is a multifactorial phenomenon that requires a dynamic balance between flexible updating and cognitive stabilization. Understanding the precise effects of DA on these subcomponent processes is not straightforward, partly because the relationship between DA and performance is nonlinear and inverted-U–shaped, with both excessive as well as insufficient levels impairing performance. In addition, effects of DA depend on the brain

Conclusions

This review highlights the complex nature of the relationship between DA and cognitive control and summarizes the research that begins to elucidate the factors that contribute to this complex relationship. We emphasize two factors. First, distinct optimum levels of DA exist for different cognitive functions. Second, cognitive control is a multifactorial phenomenon, requiring a dynamic balance between cognitive stability and cognitive flexibility. Current research is beginning to suggest that

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