Reward signals downstream of dopamine D1 receptors

It-is well known that dopamine is necessary for motor function, reward-motivated behaviors. The principal target of dopamine is medium spiny neurons (MSNs), which are a special type of GABAergic inhibitory cell that represents,90% of the neurons within the striatum, including the nucleus accumbens (NAc). There is a distinct class of spatially intermixed MSNs that express dopamine type 1 or 2 receptors (DlR-MSNs or D2R-MSNs, respectively). The D1R-MSN and D2R-MSN pathways control the dynamic balance in the basal ganglia circuit. D1R is coupled -to adenylate cyclase through Golf to activate protein kinase A (PKA), whereas D2R inhibits adenylate cyclase through Gi. Although PKA has been implicated in reward signals downstream of D1Rs by pharmacological approaches, there is no direct evidence indicating that PKA in DlR-MSNs regulates neuronal excitability and reward-related behaviors. We have established the system in which enzymatic activity can be manipulated in the NAc under the control of specific promoters for DlR-MSNs using adeno-associated virus (AAV)-mediated conditional'transgenic techniques. We have also found novel PKA substrates in dopamine receptor signaling using phosphoproteomic approach. This review article focuses on the PKA and its substrates to understand dopamine-related signals in the MSNs. We discuss phosphoproteomic approaches for' comprehensively screening of dopamine signaling. Finally, we highlight RapI pathway as a novel reward signal in vivo.