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Dopamine regulates the activity of neural networks in the prefrontal cortex that process working memory information, but its precise biophysical actions are poorly understood. The present study characterized the effects of dopamine on GABAergic inputs to prefrontal pyramidal neurons using whole-cell patchclamp recordings in vitro. In most pyramidal cells, dopamine had a temporally biphasic effect on evoked IPSCs, producing an initial abrupt decrease in amplitude followed by a delayed increase in IPSC amplitude. Using receptor subtype-specific agonists and antagonists, we found that the initial abrupt reduction was D2 receptor-mediated, whereas the late, slower developing enhancement was D1 receptor-mediated. Linearly combining the effects of the two agonists could reproduce the biphasic dopamine effect. Because D1 agonists enhanced spontaneous (sIPSCs) but did not affect miniature (mIPSCs) IPSCs, it appears that D1 agonists caused larger evoked IPSCs by increasing the intrinsic excitability of interneurons and their axons. In contrast, D2 agonists had no effects on sIPSCs but did produce a significant reduction in mIPSCs, suggestive of a decrease in GABA release probability. In addition, D2 agonists reduced the postsynaptic response to a GABA A agonist. D1 and D2 receptors therefore regulated GABAergic activity in opposite manners and through different mechanisms in prefrontal cortex (PFC) pyramidal cells. This bidirectional modulation could have important implications for the computational properties of active PFC networks.

The ionic mechanisms by which dopamine (DA) regulates the excitability of layers V-VI prefrontal cortex (PFC) output neurons (including those that project to the nucleus accumbens) were investigated in rat brain slices using in vitro intracellular recording techniques. DA or the D1 receptor agonist SKF38393, but not the D2 agonist quinpirole, reduced the first spike latency and lowered the firing threshold of the PFC neurons in response to depolarizing current pulses. This was accomplished by enhancing the duration of a tetradotoxinsensitive, slowly inactivating Na+ current and attenuating a slowly inactivating, outwardly rectifying, dendrotoxin-sensitive K+ current. Furthermore, D1 receptor stimulation attenuated high-threshold Ca2+ spike(s) (HTS) evoked primarily from the apical dendrites of these PFC neurons. Taken together, these data suggest that D1 receptor stimulation on layers V-VI pyramidal PFC neurons: (1) restricts the effects of inputs to the apical dendrites of these neurons by attenuating the dendritic HTS-mediated amplification of such inputs; and (2) potentiates the influence of local inputs from neighboring deep layers V-VI neurons by enhancing the slowly inactivating Na+ current and attenuating the slowly inactivating K+ current. By influencing the input/output characteristics of PFC-->NAc neurons, DA may play an important role in the processes through which PFC signals are translated into action.

. Mechanisms of dopamine activation of fast-spiking interneurons that exert inhibition in rat prefrontal cortex. J Neurophysiol 88: 3150 -3166, 2002. 10.1152/jn.00335.2002. Prefrontal cortical dopamine (DA) modulates pyramidal cell excitability directly and indirectly by way of its actions on local circuit GABAergic interneurons. DA modulation of interneuronal functions is implicated in the computational properties of prefrontal networks during cognitive processes and in schizophrenia. Morphologically and electrophysiologically distinct classes of putative GABAergic interneurons are found in layers II-V of rat prefrontal cortex. Our whole cell patch-clamp study shows that DA induced a direct, TTX-insensitive, reversible membrane depolarization, and increased the excitability of fast-spiking (FS) interneurons. The DAinduced membrane depolarization was reduced significantly by D1/D5 receptor antagonist SCH 23390, but not by the D2 receptor antagonist (Ϫ)sulpiride, D4 receptor antagonists U101958 or L-745870, ␣1-adrenoreceptor antagonist prazosin, or serotoninergic receptor antagonist mianserin. The D1/5 agonists SKF81297 or dihydrexidine, but not D2 agonist quinpirole, also induced a prolonged membrane depolarization. Voltage-clamp analyses of the voltagedependence of DA-sensitive currents, and the effects of changing [K ϩ ] O on reversal potentials of DA responses, revealed that DA suppressed a Cs ϩ -sensitive inward rectifier K ϩ current and a resting leak K ϩ current. D1/D5, but not D2 agonists mimicked the suppressive effects of DA on the leak current, but the DA effects on the inward rectifier K ϩ current were not mimicked by either agonist. In a subgroup of FS interneurons, the slowly inactivating membrane outward rectification evoked by depolarizing voltage steps was also attenuated by DA. Collectively, these data showed that DA depolarizes FS interneurons by suppressing a voltage-independent 'leak' K ϩ current (via D1/D5 receptor mechanism) and an inwardly rectifying K ϩ current (via unknown DA mechanisms). Additional suppression of a slowly inactivating K ϩ current led to increase in repetitive firing in response to depolarizing inputs. This D1-induced increase in interneuron excitability enhances GABAergic transmission to PFC pyramidal neurons and could represent a mechanism via which DA suppresses persistent firing of pyramidal neurons in vivo.

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