Intraportal delivery of serotonin enhanced net hepatic glucose uptake (NHGU) during a hyperinsulinemic hyperglycemic clamp, but serotonin elevated catecholamines and can cause gastrointestinal distress. We hypothesized that the selective serotonin reuptake inhibitor (SSRI) fluvoxamine would enhance NHGU without side effects. Arteriovenous difference and tracer ([3-(3)H]glucose) techniques were used in conscious 42-h-fasted dogs. Experiments consisted of equilibration (-120 to -30 min), basal (-30 to 0 min), and experimental (EXP; 0-270 min) periods. During EXP, somatostatin, fourfold basal intraportal insulin, basal intraportal glucagon, and peripheral glucose (to double the hepatic glucose load) were infused. Saline (SAL) was infused intraportally during 0-90 min (P1), and fluvoxamine was infused intraportally at 0.5, 1, and 2 mug.kg(-1).min(-1) from 90 to 150 (P2), 150 to 210 (P3), and 210 to 270 (P4) min, respectively, in the FLUV group (n = 8). The SAL group (n = 9) received intraportal saline during 0-270 min. NHGU in SAL was 13.9 +/- 1.7 and 17.0 +/- 2.0 mumol.kg(-1).min(-1) in P3-P4, respectively, while NHGU in FLUV averaged 19.7 +/- 2.8 and 26.6 +/- 3.0 mumol.kg(-1).min(-1) (P < 0.05 vs. SAL). Net hepatic carbon retention was greater (P < 0.05) in FLUV than in SAL (17.6 +/- 2.6 vs. 13.9 +/- 2.7 and 23.8 +/- 3.0 vs. 14.4 +/- 3.3 mumol.kg(-1).min(-1) in P3-P4, respectively), and final hepatic glycogen concentrations were 50% greater in FLUV (P < 0.005). Nonhepatic glucose uptake was greater in SAL than in FLUV at 270 min (P < 0.05). Catecholamine concentrations remained basal, and the animals evidenced no distress. Thus fluvoxamine enhanced NHGU and hepatic carbon storage without raising circulating serotonin concentrations or causing stress, suggesting that hepatic-targeted SSRIs might be effective in reducing postprandial hyperglycemia in individuals with diabetes or impaired glucose tolerance.