Mechanisms underlying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex

Typically, D1 and D2 dopamine (DA) receptors exert opposing actions on intracellular signaling molecules and often have disparate physiological effects; however, the factors determining preferential activation of D1 versus D2 signaling are not clear. Here, in vitro patch-clamp recordings show that DA concentration is a critical determinant of D1 versus D2 signaling in prefrontal cortex (PFC). Low DA concentrations (<500 nM) enhance IPSCs via D1 receptors, protein kinase A, and cAMP. Higher DA concentrations (>1 muM) decrease IPSCs via the following cascade: D2-->G(i)-->platelet-derived growth factor receptor -->up arrow phospholipase C-->up arrowIP(3)-->up arrowCa(2+)-->down arrow dopamine and cAMP-regulated phosphoprotein-32-->up arrowprotein phosphatase 1/2A-->down arrowGABA(A). Blockade of any molecule in the D2-linked pathway reveals a D1-mediated increase in IPSCs, suggesting that D1 effects are occluded at higher DA concentrations by this D2-mediated pathway. Thus, DA concentration, by acting through separate signaling cascades, may determine the relative amount of cortical inhibition and thereby differentially regulate the tuning of cortical networks.