A healthy acute stress response requires both rapid increase and rapid clearance of blood corticosteroids. We previously showed that regulators of G-protein signaling 4 (RGS4), which decreases in the paraventricular nucleus (PVN) during acute stress, forms a complex with the GABA(B) receptor. In the present study, we show that this decrease in RGS4 levels in the PVN during an acute stress response facilitates the return of blood corticosteroids to basal levels. Moreover, the effect of RGS4 decrease is attenuated by a GABA(B) receptor antagonist. These results suggest that RGS4 in the PVN regulates blood corticosteroid-related GABA(B) receptor signaling during the acute stress response. (C) 2016 Elsevier Inc. All rights reserved.