7 February 2007. In the brain you can have too much of a good thing, especially when it comes to dopamine. Scientists have known for some time that stimulating D1 dopamine receptors in the prefrontal cortex (PFC) has a positive effect on working memory, but that having too much dopamine, or too little, impairs cognitive performance. Although this response has been well documented in rodents, monkeys, and humans, the molecular and cellular bases for this relationship have not been well defined, but in yesterday's Nature Neuroscience, Amy Arnsten and colleagues at Yale University show this need for "just the right amount of dopamine" working at the cellular level and they implicate the cellular messenger cyclic AMP in the process. Their findings are particularly relevant to schizophrenia, which features PFC dysfunction, because recent research suggests that people with the illness may have different baseline levels of dopamine.
The relationship between PFC dopamine and cognitive performance traces an "inverted U," or bell-shaped curve. As dopamine levels increase, cognitive performance improves, reaching a peak and then declining. Where we want to be for ideal performance is at the peak of the inverted U. Work from Danny Weinberger’s group at the National Institute of Mental Health, Bethesda, Maryland, showed that one’s baseline position on the inverted U is related to variations in catechol-O-methyltransferase (COMT), an enzyme that degrades dopamine (see Mattay et al., 2003). The most common variant of COMT has a valine at position 158, but in a substantial percentage of the population this is replaced with a methionine. This variation has been associated with weaker frontal lobe function under nonstress conditions, and to a less consistent degree with psychosis, not just in schizophrenia but in Alzheimer's disease and brain injury.
Since the methionine variant of COMT is less catalytically active, those who carry it may have higher baseline levels of dopamine. This is likely helpful under basal conditions, but may be a liability during stress. “Under stressful conditions, there is more dopamine released, and those people with the methionine substitution are now on the downward part of the inverted U and their cognition is less than optimal,” said Arnsten in an interview with SRF. “Of course, this is also related to the medications aimed at trying to improve cognitive abilities because these are the very functions that are so deeply impaired in patients with this illness and are often those that interfere most with quality of life, such as the ability to get and hold a job. So understanding them is very important,” Arnsten said.
To address the cellular basis for the inverted U, first author Susheel Vijayraghavan and colleagues measured how dopamine affects firing patterns in neurons of the prefrontal cortex as primates perform a spatial working memory task. During the memory task, individual neurons of the PFC fire in a spatially specific manner as the subject waits to move its eyes to a memorized visuospatial target. Under optimal conditions, PFC neurons are spatially tuned—that is, they will fire for a preferred spatial position but not for other spatial positions. Vijayraghavan and colleagues administered varying doses of agonists specific for the D1 variant of the dopaminergic receptor (see SRF related news story) while simultaneously recording the single unit activity of PFC neurons. They found that low levels of dopamine agonists suppress neuronal firing related to the nonpreferred spatial positions, thus enhancing spatial tuning. But as the levels of agonist were increased, firing was suppressed for the preferred as well the nonpreferred spatial positions, thus eroding tuning. “What we saw is that dopamine D1 suppresses the response to irrelevant information; in other words, it increases the signal-to-noise, but if you have too much dopamine, then it erodes the signal as well as the noise,” said Arnsten.
The researchers were able to confirm that the inverted U was specific to dopamine D1 receptors because they could abolish the effect using specific D1 antagonists. They also determined that the second-messenger cAMP, but not protein kinase C, is necessary for the response, implicating signaling through G-protein signaling cascades. Both cAMP and protein kinase C have been shown to mediate dopamine responses in various neurons and experimental settings.
Arnsten believes that these findings are particularly relevant to the study and treatment of schizophrenia because they may explain the link between the disease and stress, which can lead to elevations in dopamine (see SRF related news story). “Our lab has shown for years that stress profoundly impairs cognitive functioning of the prefrontal cortex and, of course, stress can precipitate symptoms of the disease in young people. If we understand why the cortex goes offline in normal people and why people with schizophrenia are particularly sensitive to this, then we may have clues to protect against it,” she said.—Tom Fagan.
Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AFT. Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nature Neuroscience. 2007 February 4; Accelerated online publication. Abstract