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Background: Dopamine (DA) and serotonin (5-HT) are released in cortex under similar circumstances, and many psychiatric drugs bind to both types of receptors, yet little is known about how they interact., Methods: To characterize the nature of these interactions, the current study used in vitro patch-clamp recordings to measure the effects of DA and/or 5-HT on pyramidal cells in layer V of the medial prefrontal cortex., Results: Either DA or 5-HT applied in isolation increased the evoked excitability of prefrontal cortex neurons, as shown previously. Coapplication of DA and 5-HT produced either a larger increase in excitability than when either was given alone or a significant decrease that was never observed when either was given alone. Dopamine or 5-HT also "primed" neurons to respond in an exaggerated manner to the subsequent application of the other monoamine., Conclusions: These data reveal the unappreciated interactive nature of neuromodulation in cortex by showing that the combined effects of DA and 5-HT can be different from their effects recorded in isolation. On the basis of these findings, we present a theory of how DA and 5-HT might synergistically modulate cortical circuits during various tasks., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

There is now general consensus that at least some of the cognitive deficits in schizophrenia are related to dysfunctions in the prefrontal cortex (PFC) dopamine (DA) system. At the cellular and synaptic level, the effects of DA in PFC via D1- and D2-class receptors are highly complex, often apparently opposing, and hence difficult to understand with regard to their functional implications. Biophysically realistic computational models have provided valuable insights into how the effects of DA on PFC neurons and synaptic currents as measured in vitro link up to the neural network and cognitive levels. They suggest the existence of two discrete dynamical regimes, a D1-dominated state characterized by a high energy barrier among different network patterns that favors robust online maintenance of information and a D2-dominated state characterized by a low energy barrier that is beneficial for flexible and fast switching among representational states. These predictions are consistent with a variety of electrophysiological, neuroimaging, and behavioral results in humans and nonhuman species. Moreover, these biophysically based models predict that imbalanced D1:D2 receptor activation causing extremely low or extremely high energy barriers among activity states could lead to the emergence of cognitive, positive, and negative symptoms observed in schizophrenia. Thus, combined experimental and computational approaches hold the promise of allowing a detailed mechanistic understanding of how DA alters information processing in normal and pathological conditions, thereby potentially providing new routes for the development of pharmacological treatments for schizophrenia.