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Microdialysis studies have demonstrated that the release of serotonin (5-hydroxytryptamine, 5-HT) in the serotonergic projection areas increases during waking and decreases during sleep in rat and cat, suggesting that 5-HT plays an important role in modulation of sleep. Although it might be expected that 5-HT release is also decreased during general anesthesia, the functional contribution of serotonergic neurons in pharmacological effects of volatile anesthetics has not been fully investigated.Using an in vivo microdialysis technique, we measured extracellular 5-HT in rat frontal cortex during waking, slow-wave sleep, and isoflurane anesthesia. To assess the involvement of the serotonergic system in the hypnotic action of isoflurane, the concentration of isoflurane required for loss of righting reflex was determined with or without pretreatment of fluoxetine hydrochloride, a selective 5-HT reuptake inhibitor.During slow-wave sleep and isoflurane anesthesia (0.1–1.5 MAC), 5-HT release decreased to 21%–44% of that during the waking state. Loss of righting reflex occurred at significantly higher isoflurane concentrations in fluoxetine-treated rats (0.76% ± 0.03% [n = 8]) than in control rats (0.60% ± 0.01% [n = 8]).It is suggested that a change in the activity of the serotonergic system in the brain is involved in the hypnotic action of isoflurane.