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Seamans, Jeremy Dopamine Modulation of Prefrontal Cortex I: Effects on Intrinsic and Synaptic Currents The prefrontal cortex (PFC) and its dense dopaminergic input are critically involved in working memory. Both sub- and supranormal stimulation of dopaminergic receptors in the PFC disrupt delay task performance, which is indicative of working memory functioning. In vivo, in behaving primates, dopamine (DA) has been shown to significantly enhance delay-period activity (~175%) relative to background firing via a D1 receptor mechanism. Paradoxically, in the anesthetized preparation no such excitation is observed, but rather DA has a short-lived inhibitory effect. To gain insights into the complex and contradictory actions of DA in the PFC and its functional role in working memory, we used a combination of in vitro patch-clamp recordings from PFC neurons with detailed compartmental modeling. In many PFC pyramidal neurons, DA produced a long-lasting enhancement of firing. Voltage-clamp analyses of pharmacologically isolated currents revealed that this long-lasting enhancement was due primarily to D1- mediated alterations in a persistent Na+ current (INAP). D1 agonists shifted the activation of INAP to more hyperpolarized potentials while slowing the time constant of inactivation. Moreover, D1 agonists produced a 30-40% increase in isolated GABAA IPSPs and isolated NMDA EPSCs, while producing a non-significant depression of non-NMDA EPSCs. These data indicate that the effects of DA are not simply excitatory or inhibitory. Because INAP and NMDA but not GABAA conductances increase with depolarization, the effect of DA on PFC neurons may depend critically on their state of activation. Thus, DA might differentially affect activity under conditions of low versus high excitatory drive. A computational network study was conducted to test these hypotheses and to analyze the functional consequences of DA action in the PFC in more detail (Durstewitz et al., PFC II).
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