Regulation of several voltage-gated conductances may contribute to these diverse effects. In PFC pyramidal neurons, activation of D1 receptors reduces K+ currents carried by inward-rectifying (Dong et al., 2004; Witkowski et al., 2008) and voltage-activated (Dong and White, 2003; Dong et al., 2004, 2005; Yang and Seamans, 1996) K+ channels, which are respectively expected to facilitate transitions to up states and help sustain them once achieved. D1 receptor activation has been selleck chemical shown to increase (Gorelova and Yang, 2000; Yang and Seamans, 1996), suppress (Geijo-Barrientos and Pastore, 1995; Gulledge and Jaffe, 2001; Rotaru et al.,

2007), or exert no effect (Maurice et al., 2001) on the amplitude of persistent voltage-activated Na+ currents. This diversity may result in part from the voltage dependence of this modulation (Gorelova and Yang,

2000). In addition, D1 receptor agonists inhibit transient voltage-sensitive Na+ currents (Maurice et al., 2001; Peterson et al., 2006; but see Gulledge and Jaffe, 2001; Gulledge and Stuart, 2003). Some of these effects MK-8776 mw are consistent with the differential modulation of transient and persistent Na+ currents by PKA and PKC (Chen et al., 2006; Franceschetti et al., 2000), which are both engaged by D1-like receptors in PFC neurons and together exert a net positive influence on membrane excitability (Franceschetti et al., 2000). Modulation of Na+ channels can not only influence action potential initiation and discharge rate, but also the amplitude of synaptic

potentials and their active propagation along dendrites (Rotaru et al., 2007). Electrophysiological and Ca2+ imaging experiments in deep layer pyramidal neurons also revealed that D1-like receptor agonists suppress dendritic Ca2+ influx through CaV1, CaV2.2, and possibly CaV2.1 via PKC or direct protein interaction CYTH4 (Kisilevsky et al., 2008; Yang and Seamans, 1996; Young and Yang, 2004; Zhou and Antic, 2012). However, other studies failed to detect any DA modulation of dendritic Ca2+ transients evoked by back-propagating action potentials (Gulledge and Stuart, 2003) or reported PKA-dependent potentiation of CaV1 currents evoked by subthreshold somatic current injection (Young and Yang, 2004). Thus, the reported effects of D1-like receptors on individual ionic conductances in PFC neurons are diverse and a coherent view of the modulatory changes that underlie the excitatory effects of these receptors has yet to emerge. The ionic conductances that underlie the modulatory effects of D2 receptors in PFC pyramidal neurons have not been investigated as extensively. In instances in which D2-like receptor stimulation promotes the intrinsic excitability of subpopulations of L5 pyramidal cells, the effects have been attributed to suppression of Kir channels (Dong et al.