Dopamine

The Role of Dopamine in Cognition

The nigrostriatal and mesocortical dopamine systems are well known to play an important role in the cognitive processes of working memory and cognitive control. However, accumulating evidence indicates that the effects of dopaminergic drugs are complex: They can improve or impair cognitive function. We have demonstrated such contrasting effects both in young, healthy volunteers (Kimberg et al., 1997), as well as in patients with Parkinson’s disease (Cools et al., 2006), a movement disorder characterized by severe dopamine depletion. Work in our lab has demonstrated that the relationship between dopamine and cognitive performance is qualified by at least three factors. First, drug effects appear dependent on the type of task: while the administration of dopaminergic drugs can improve performance on some tasks, it can simultaneously impair performance on other tasks in the same subjects. Second, the effects vary depending on dopamine receptor selectivity of the drug under study. Thus, stimulation of dopamine D1 and D2 receptors has dissociable effects on distinct cognitive functions. Third, dopaminergic drugs can improve function in some individuals while impairing the same function in other individuals.

The aim of our research has been to characterize these complex, sometimes paradoxical effects of dopaminergic drugs in both healthy subjects as a function of task demands, receptor specificity, and individual differences in baseline working memory capacity. In our studies, both performance and brain activity using fMRI is assessed. We have found that drug effects differ whether the task requires cognitive flexibility or cognitive stability. We have hypothesized that cognitive flexibility and stability are mediated by two separate mechanisms that nevertheless work together: DA would promote stability or flexibility depending on the neural site of modulation. Specifically, DA receptor stimulation in the prefrontal cortex (PFC) is hypothesized to promote stability by increasing distractor resistance. Conversely, DA in the striatum is hypothesized to promote flexibility by allowing the updating of newly relevant representations. As an initial test of these hypotheses, we performed a fMRI pharmacological challenge study with the DA D2 agonist bromocriptine in healthy young controls (Cools et al., 2007). We assessed the effects of bromocriptine on task-related neural activity and performance on a novel delayed match-to-sample paradigm that enabled the separate assessment of attentional switching (requiring cognitive flexibility) and resistance to distraction (requiring cognitive stability). We found that bromocriptine improved attentional switching and potentiated switch-related striatal activity in the low working memory capacity subjects but impaired switching and attenuated switch-related activity in the high working memory capacity subjects. Furthermore, the effects of bromocriptine on distractor-related activity could also be predicted from baseline working memory capacity; however, this time, the effects were observed only in the PFC and not in the striatum. Bromocriptine potentiated distractor-related PFC activity in low working memory capacity subjects, but attenuated it in high working memory capacity subjects. Thus, the data strongly supports our original hypotheses.

We have hypothesized that our consistent findings that dopaminergic drug effects differ depending on individual variation in baseline working memory capacity is due to individual variation in baseline dopamine function. To test this hypothesis (Cools et al., 2008), a subgroup of high- and a subgroup of low working memory capacity healthy subjects underwent a PET scan with the radiotracer 6-[18F]fluoro-L-m-tyrosine (FMT). This substance is a substrate of dopamine synthesis capacity and uptake of the tracer reflects the degree to which DA is synthesized in the striatum. Subjects with low working memory capacity had significantly lower dopamine synthesis capacity in the left caudate nucleus than did subjects with high working memory capacity. Dopamine synthesis capacity was also lower for low working memory capacity subjects in the left putamen, the right caudate nucleus and the right putamen, but these effects did not reach significance, with the left lateralization of the effect possibly reflecting the verbal nature of the task. These data provide empirical evidence for the pervasive but hitherto untested hypothesis that the dependency of dopaminergic drug effects on baseline working memory capacity reflects differential baseline levels of dopamine function.

Estradiol enhances dopamine activity in the brain, estradiol levels are higher in the prefrontal cortex than other cortical areas, and studies of post-menopausal women on estrogen suggest a direct link between estrogen and working memory. Thus, we have tested the hypothesis that estradiol’s effects on working memory are mediated by the modulation of prefrontal dopamine activity (Jacobs & D'Esposito, 2011). On 24 young, healthy women, fMRI scans were performed during a working memory task at two points in their menstrual cycle when their estradiol levels, based on blood samples, were at their lowest and highest. It was found that estradiol levels modulated prefrontal cortical activity depending on one’s baseline dopamine levels, as measured by the COMT enzyme in the blood. The extent of this modulation predicted an individual's performance on the working memory task. These results indicate that a full model of cognition will require incorporating the role of brainstem neuromodulatory and hormonal systems.

Dopamine is of fundamental importance to the etiology of various neurocognitive disorders such as Parkinson’s disease, attention deficit hyperactivity disorder, schizophrenia, and drug addiction. A further understanding of the relationship between dopamine and cognition should further our understanding of the mechanisms underlying cognitive and behavioral deficits in these disorders and provide insight into novel approaches to treating such deficits with medications targeted at specific neurotransmitter systems (McDowell et al., 1998).

Key References:

Kimberg D, D’Esposito M, Farah MJ. Effects of bromocriptine on human subjects depend on working memory capacity., NeuroReport, 8:3581-3585, 1997.

Cools R, Altamirano L, D'Esposito, M. Reversal learning in Parkinson’s disease depends on medication status and outcome valence, Neuropsycholgia, 44:1663-1673, 2006.

Cools, R, Sheridan, M, Jacobs, EC, D'Esposito M. Impulsive personality predicts dopamine-dependent changes in frontostriatal activity during component processes of working memory, Journal of Neuroscience, 27:5506-14, 2007.

Cools R, Gibbs SE, Myiakawa A, Jagust W, D’Esposito M. Working memory capacity predicts dopamine synthesis in the human striatum, Journal of Neuroscience, 28:1208-1212, 2008

Cools R, Gibbs SE, Myiakawa A, Jagust W, D’Esposito M. Working memory capacity predicts dopamine synthesis in the human striatum, Journal of Neuroscience, 28:1208-1212, 2008.

Jacobs E, D’Esposito M. Estrogen shapes dopamine-dependent cognitive processes: implications for women’s health, Journal of Neuroscience, 31(14):5286-5293, 2011.

McDowell S, Whyte J, D’Esposito M, Differential effects of a dopaminergic agonist on prefrontal function in head injury patients, Brain, 121:1155-1164, 1998.