cAMP response-element binding protein (CREB) functions in hippocampal synaptic plasticity and memory formation. However, it remains unknown whether intravenous anesthetics modulate CREB. The present study aimed to examine the effects of intravenous anesthetics on CREB phosphorylation in the mouse hippocampus. CREB phosphorylation was examined in hippocampal slices with and without pharmacological or intravenous anesthetics via immunoblotting. In a dose-response experiment, the concentrations of intravenous anesthetics ranged from 10(-9) to 10(-4) mol/l for 1 h. For the time-response experiment, these slices were incubated with 5x10(-6) mol/l of propofol for 0, 1, 2, 5, 7, 9, 12, 15, 30 and 60 min. In order to examine whether CREB phosphorylation could be recovered following washing out the propofol, the slices were incubated in plain artificial cerebrospinal fluid at different time durations following 5 min incubation with propofol. Propofol, etomidate, ketamine and midazolam inhibited CREB phosphorylation (P<0.05) in a time- and dose-dependent manner. This inhibition was reversible following the removal of propofol, and was rescued by CREB phosphorylation (P<0.05). The decrease in CREB phosphorylation revealed additive effects with 100 mu M of chelerythrine and 20 mu M of PD-98059, and the etomidate-induced decrease in CREB phosphorylation was blocked by 1 mM of NMDA. However, 0.1 mu M of phorbol 12-myristate 13-acetate, 50 mu M of U 73122, 100 mu M of carbachol and 10 mu M of MK801 were ineffective in the anesthetic-induced decrease in CREB phosphorylation. Intravenous anesthetics markedly decreased CREB phosphorylation in the mouse hippocampus, which was most likely via the protein kinase C and mitogen activated protein kinase pathways. This suggests that CREB represents a target for anesthetic action in the brain.