Background: Extracellular signal-regulated kinase 1/2 (ERK1/2) has been implicated in learning and memory; however, whether intravenous anesthetics modulate ERK1/2 remains unknown. The aim of this study was to examine the effect of several intravenous anesthetics on the phosphorylation of ERK1/2 in the hippocampus of adult mice. Methods: Western blotting was used to examine cellular levels of phosphorylated and unphosphorylated ERK1/2 in mouse hippocampus slices, which were incubated with or without anesthetics including propofol, etomidate, ketamine and midazolam, a protein kinase C (PKC) activator or inhibitor, or phospholipase C (PLC) activator or inhibitor. Results: Propofol, etoMidate, ketamine and midazolam reduced phosphorylation of ERK1/2 in a time dependent manner. Washing out propofol after 5 min increased ERK1/2 phosphorylation. The anesthetic-induced depression of ERK1/2 phosphorylation was blocked by 0.1 mu M phorbol-12-myristate 13-acetate (an activator of PKC), 50 mu M U73122 (an inhibitor of PLC). The anesthetic-induced depression of ERK1/2 phosphorylation was blocked by 1 mMN-methyl-D-aspartate (NMDA). Whereas 100 mu M chelerythrine (an inhibitor of PKC)and 100 AM carbachol (an activator of PLC) and 20 mu M PD-98059 (an inhibitor of MEK) had additive effects on propofol-induced inhibition of ERK1/2 phosphorylation. In contrast, 10 mu M MK801 (a NMDA receptor antagonist) did not block anesthetic-induced inhibition of ERK1/2 phosphorylation. Conclusion: Intravenous anesthetics markedly decreased phosphorylation of ERK1/2 in mouse hippocampal slices, most likely via the NMDA receptor, and PLC- and PKC-dependent pathways. Thus, ERK1/2 represents a target for anesthetics in the brain. (C) 2016 Published by Elsevier Ltd.