Mechanisms Underlying Differential D1 versus D2 Dopamine Receptor Regulation of Inhibition in Prefrontal Cortex

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Abstract
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 vitropatch-clamp recordings show that DA concentration is a critical determinant of D1 versus D2 signaling in prefrontal cortex (PFC). Low DA concentrations (1 μm) decrease IPSCs via the following cascade: D2→Gi→platelet-derived growth factor receptor→↑phospholipase C→↑IP3→↑Ca2+→↓dopamine and cAMP-regulated phosphoprotein-32→↑protein phosphatase 1/2A→↓GABAA. 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.