19 February 2009. Schizophrenia researchers are on very close terms with D2 dopamine receptors, culprits in propagating the positive symptoms of schizophrenia and the target of all currently approved antipsychotic drugs. Their D1 cousins may not be so innocent either—there is evidence that their faulty operation in prefrontal cortex can contribute to cognitive deficits and possibly negative symptoms in the disorder (reviewed in SRF Current Hypothesis by A. Abi-Dargham).
While previous research has shown that manipulating prefrontal D1 transmission affects working memory, Torkel Klingberg at the Karolinska Institutet, Stockholm, Sweden, and colleagues have now found that the opposite may also be true. Writing in the February 6 issue of Science, they report that, in humans, reduction in D1 receptor binding occurs during working memory training, suggesting that downregulation of those receptors is crucial for optimal cognition. This provides indirect support for the notion that upregulation of D1 receptors could underlie working memory deficits in schizophrenia.
First author Fiona McNab and colleagues measured dopamine receptor levels after healthy volunteers had been put through intensive working memory training. At baseline, and at the end of the training, the researchers used positron emission tomography (PET) to measure radioligand binding to both D1 and D2 receptors using the compounds SCH23390 and Raclopride, respectively. They used functional MRI measurements to identify brain regions involved in working memory, then focused on those regions of interest in the PET scans. For D1 measurements there were five regions of interest, regions where D1 is the predominant variety of dopamine receptor: the right and left posterior cortices (including parietal, temporal, and occipital cortices); the right dorsolateral prefrontal cortex (including right middle frontal gyrus and right superior frontal gyrus); the left frontal cortex (including left middle frontal gyrus); and the right ventrolateral prefrontal cortex (including the right inferior frontal gyrus). For D2 measurements they focused on the bilateral caudate and putamen.
After five weeks of intensive working memory training, in which 13 healthy male volunteers (aged 20 to 28) performed tasks that were close to their personal maximal difficulty level for 35 minutes each day, McNab and colleagues found that working memory capacity had improved. The change did not correlate with changes in D2 binding, but it did correlate with D1 binding decreases, particularly in four of the five regions of interest (both posterior cortices, the right ventrolateral and right dorsolateral prefrontal). “This is consistent with the finding that low doses of a D1 antagonist enhance the delay activity of prefrontal neurons during the performance of working memory tasks,” write the authors.
The work supports the idea that D1 receptors may contribute to working memory deficits in schizophrenia. In patients with the disease, D1 levels are indeed reportedly higher in the dorsolateral prefrontal cortex (see Abi-Dargham et al., 2002), which might compromise working memory tasks, according to the new research. The relationship between dopaminergic function and schizophrenia may be even more complex, however, since there is now considerable evidence for an inverted U type of dose response to dopamine—at both high and low levels cognition is impaired. Maintaining just the right balance of dopamine may be critical, and genetic or environmental stress that shifts that dynamic may predispose individuals to schizophrenia (see SRF related news story). The role played by the two receptors complicates the relationship even more, since they can often have opposite downstream effects. Any imbalance between D1-D2 might, therefore, put individuals at risk for the cognitive, positive, and negative symptoms seen in schizophrenia (for a recent review, see Durstewitz and Seamans, 2008). The study by McNab and colleagues hints that working memory training might actually help with symptoms, by reducing D1 receptor levels, but that idea needs to be empirically tested (see SRF related news story).—Tom Fagan.
McNab F, Varrone A, Farde L, Jucaite A, Bystritsky P, Forssberg H, Klingberg T. Changes in cortical dopamine D1 receptor binding associated with cognitive training. Science. 2009, February 6; 323:800-802. Abstract