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The serotonergic system may play a role during general anesthesia. Furthermore, alterations in serotonergic neurotransmission in the hippocampus have been linked to depression and anxiety as well as to changes in arousal and cognition. Little is known about the effects of volatile anesthetics on hippocampal serotonin (5-HT) levels. In this study we examined the effects of isoflurane on hippocampal 5-HT levels in mice. Adult male 129/SvEv mice were exposed to either isoflurane 1 or 1.5 minimum alveolar concentration (MAC) both in 40% O2 in air or to 40% O2 in air alone (control) for a period of 80 min, and hippocampal 5-HT levels were measured by microdialysis coupled with high performance liquid chromatography. Within 20–40 min of administration, both doses of isoflurane similarly produced a significant decrease in hippocampal 5-HT to 41.5% ± 11.0% and 36.4% ± 13.9% of the baseline level in the isoflurane 1 MAC and 1.5 MAC groups, respectively. Furthermore, when additional dialysates were obtained on termination of anesthesia in the isoflurane 1.5 MAC group, the decrease in extracellular 5-HT levels persisted for several hours. To determine if isoflurane-induced changes in extracellular 5-HT involve the serotonin transporter (SERT), similar microdialysis studies were performed in C57BL/6 wild-type (SERT +/+) and homozygous SERT knockout (SERT −/−) mice exposed to either 1 MAC isoflurane in 40% O2 in air or to 40% O2 in air alone for a period of 80 min. Isoflurane produced a significant decrease in hippocampal 5-HT in SERT +/+ and SERT −/−, and this decrease was larger in SERT −/− compared with SERT +/+: to 22.4% ± 8.5% versus 50.2% ± 17.4% of the baseline 5-HT level, respectively. These data suggest that isoflurane produces a decrease in hippocampal 5-HT, independent of SERT function.