STUDY OBJECTIVES: Extensive data implicate serotonin (5-hydroxytryptamine [5-HT]) in the regulation of sleep. Jouvet has hypothesized that 5-HT promotes wakefulness, yet is necessary for subsequent non-rapid eye movement (NREM) sleep, actions he proposes to be mediated by sleep factors. Studies in rat support this dual role for 5-HT. The objectives of this study were to (1) determine effects of serotonergic activation on sleep of mice and (2) elucidate a potential role for the cytokine interleukin-6 as a sleep factor mediating serotonergic effects on sleep. DESIGN: C57BL/6J and B6.129S6-II6(tm1Kopf)(interleukin-6 knockout [IL-6 KO]) mice were purchased from the Jackson Laboratory and instrumented for recording the electroencephalogram and body temperature. After recovery, separate groups of mice were injected intraperitoneally at either light or dark onset with vehicle or with the 5-HT precursor 5-hydroxytryptophan (5-HTP). Sleep-wake behavior was determined and body temperature recorded for 24 hours after injections. RESULTS: 5-HTP induced hypothermia in both mouse strains. When injected at dark onset, the highest dose of 5-HTP (200 mg/kg) increased NREM sleep. Light onset administration initially increased wakefulness, with increases in NREM sleep apparent only during the subsequent dark period. For most parameters, there were no differences in responses between strains. However IL-6 KO mice at some doses exhibited a greater increase in NREM sleep. CONCLUSIONS: 5-HTP alters sleep-wake behavior and body temperature of mice in a manner similar to that of rats. Increases in NREM sleep after 5-HTP are apparent only during the dark period, which may represent a fundamental property of the serotonergic system. These results suggest that 5-HT should not be considered either wake promoting or NREM sleep promoting. Rather, the role of 5-HT in the regulation of sleep-wake behavior must be considered within the context of the degree to which the system is activated and the time at which the activation occurs.