Although considerable efforts have been invested during the past several decades in elucidating the cellular mechanisms by which DA modulates
PFC function, the actions of DA and the underlying receptors and signaling pathways involved remain controversial. What is clear is that DA modulates the intrinsic excitability of both pyramidal neurons and local interneurons and that DA’s actions on the latter has historically confounded in vivo and in vitro investigations of its effects on the former (reviewed selleck compound in Seamans and Yang, 2004). In addition, PFC is composed of several functionally distinct pyramidal and nonpyramidal cell types that receive variable dopaminergic innervation along their dendritic trees and express different levels and combinations of DA receptors across cortical layers (Wang et al.,
2006). Finally, the functional implications of modulatory effects on isolated currents are often unclear due to the large number of ionic conductances that shape synaptic potentials and spike output, the dependence of these processes on membrane potential, and the complexity of the network in which these cells are embedded. In the majority of in vitro studies in which synaptic contributions are pharmacologically excluded, DA enhances the intrinsic excitability of deep layer PFC pyramidal neurons by elevating the resting membrane potential or promoting a slow but long-lasting increase in the number of action potentials evoked by somatic depolarization (Ceci et al., 1999; Gao and Goldman-Rakic, 2003; Gulledge and Jaffe, 2001; Gulledge and Stuart, 2003; Kroener et al., Selleckchem JQ1 2009; Lavin and Grace, 2001; Moore et al., 2011; Penit-Soria et al., Protein kinase N1 1987; Shi et al., 1997; Wang and Goldman-Rakic, 2004; Yang and Seamans, 1996). In most cases, DA’s actions are selectively abolished by D1-like receptor antagonists and mimicked by D1-like agonists (Chen et al., 2007; Gao and Goldman-Rakic, 2003; Gulledge and Jaffe, 2001; Gulledge
and Stuart, 2003; Kroener et al., 2009; Lavin and Grace, 2001; Penit-Soria et al., 1987; Seong and Carter, 2012; Shi et al., 1997; Tseng and O’Donnell, 2004; Witkowski et al., 2008; Yang and Seamans, 1996), implicating signaling through D1-class receptors. Moreover, some studies have indicated that D2-like receptors actively oppose D1 receptor-mediated excitation by directly suppressing intrinsic neuronal excitability (Gulledge and Jaffe, 1998; Tseng and O’Donnell, 2004). However, several other studies have assigned DA-induced increased excitability to D2-class receptors in deep layer pyramidal neurons (Ceci et al., 1999; Gee et al., 2012; Moore et al., 2011; Wang and Goldman-Rakic, 2004) and have reported a net inhibitory effect of D1-class receptors on spike output (Moore et al., 2011; Rotaru et al., 2007). In L2/3 PFC pyramidal neurons, DA was shown to promote (Henze et al.