Long-term administration of dexfenfluramine to genetically obese (ob/ob) and lean mice: body weight and brain...

The weight-reducing and brain 5-HT-depleting properties of dexfenfluramine (DFEN) or dexnorfenfluramine (DNOR) were measured in genetically obese (ob/ob) and lean mice. These agents were infused for 14 days via osmotic minipumps to mice fed either a low fat or a moderate fat diet. Weight loss was observed in only the obese mice, with DNOR more potent than DFEN. At the end of 14 days, neither agent caused a consistent change in either plasma glucose or corticosterone concentrations, although some effects of diet and differences between batches of mice were apparent. The levels of brain 5-HT, or of paroxetine binding that correlates with 5-HT level, were reduced by 24 mg DFEN/kg/day, a decline that persisted for at least 14 days after the end of treatment. Plasma and brain concentrations of DFEN and DNOR were measured on the last day of pump function. DNOR accounted for about 30% of the total drug + metabolite content, a ratio comparable to that in human plasma. Brain concentrations exceeded plasma by 10-fold at 6 mg DFEN/kg/day and by 17-fold at 24 mg DFEN/kg/day. The levels were higher in mice fed the moderate-fat compared with the low-fat diet. Depletions in brain 5-HT parameters were found only in the high-dose groups, and at brain total levels above about 20 microM.