, 2000). Interestingly, activation of D1 receptors was recently shown to prolong “up state-like” potentials evoked by repetitive glutamate uncaging on distal SPN dendrites (Plotkin et al., 2011). Generation of these regenerative plateau potentials required NMDA receptors and low-threshold CaV3 channels, which are enriched in distal dendrites and spines (Carter and Sabatini, 2004; Carter et al., 2007; Day et al., Epigenetic inhibitor molecular weight 2006), but it is currently unclear whether

the D1 receptor-evoked enhancement is mediated by direct modulation of NMDA receptors or dendritic K+ and Ca2+ conductances or both. Thus, through its actions on voltage-gated K+ and Ca2+ channels, D1 receptors promote synaptic integration and spike discharge during up states while increasing the threshold for upward transitions, effectively acting to enhance contrast between up and down states. However, Lapatinib ic50 this relatively simple and consistent view of DA’s action on dSPNs is complicated by the reported effects on voltage-gated Na+ currents, which are reduced in amplitude by DA and D1-like receptor agonists (Cepeda et al., 1995; Schiffmann et al., 1995; Surmeier et al.,

1992; Zhang et al., 1998). This observation is largely responsible for the initial conclusion that D1 receptors exert a net inhibitory action on SPN excitability (Nicola et al., 2000). The apparently conflicting actions of DA on various ionic conductances reflect some of the difficulties associated with extrapolating overall neuromodulatory effects of DA from changes in isolated conductances. Given the importance of subthreshold membrane potential fluctuations to SPN function and the inability of somatic current injection protocols

to engage distal dendritic conductances (Day et al., 2008) and to evoke state transitions in acute slices (Wilson, 2004), analyses of spike discharge modulation upon somatic depolarization may not adequately capture DA’s influence on synaptic integration and intrinsic excitability. Nevertheless, although the spike-promoting effects of D1 receptors on K+ and Ca2+ channels MycoClean Mycoplasma Removal Kit may be moderated by reduced Na+ channel availability, most of the evidence accrued to date favors models in which D1 receptors promote dSPN intrinsic excitability (Gerfen and Surmeier, 2011; Wickens and Arbuthnott, 2005). The reported effects of D2 receptor activation on isolated ionic conductances and up state potentials in SPNs largely oppose those of D1 receptors. Through their inhibitory action on PKA, D2 receptors suppress currents attributable to Kir2 channels but enhance depolarization-activated and ATP-sensitive K+ channels (Greif et al., 1995; Perez et al., 2006; Sun et al., 2000; Surmeier and Kitai, 1993), indicating that D2 receptor activation may facilitate up state transitions but stunt their duration and the depolarization achieved. D2 receptors further limit somatic excitability by decreasing Ca2+ influx through somatic CaV1 channels (Hernandez-Lopez et al., 2000; Salgado et al., 2005).