Depletion and time-course of recovery of brain serotonin after repeated subcutaneous dexfenfluramine in the mouse. A comparison with the rat

The indole-depleting effects of repeated subcutaneous doses of dexfenfluramine (D-F) (2.5, 5, 10, 20 and 40 mg/kg/day, for four days) in mice were examined with regard to the initial response and time-course of recovery and related to the pharmacokinetics of D-F and its active metabolite dexnorfenfluramine (D-NF). Steady-state plasma and brain concentrations of D-F rose dose-dependently with a metabolite-to-drug ratio averaging 0.4 in brain. This confirmed that in mice D-NF contributes less than in other species to the effects of D-F. Regional serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) contents were decreased dose-dependently 4 hr after the last injection of D-F. However, two weeks after D-F (2.5-10 mg/kg/day) brain indoles had almost totally recovered, and the long-term effects of the 20 mg/kg/day dose were completely reversed by six weeks, when significant effects are still observable in rats. Although substantial recovery was evident even at 40 mg/kg/day, 5-HT but not 5-HIAA was still slightly reduced nine weeks later. Comparative studies in rats given 2.5-20 mg/kg/day D-F indicated much more severe initial indole depletions than in mice. Brain levels of D-F and D-NF were much higher in rats than in mice. The total active drug brain concentration (D-F + D-NF) was significantly correlated with 5-HT content in both species, with approx 20 nmol/g of total drug causing 50% reduction. These findings point to species differences in D-F kinetics as a main reason for differences in the neurochemical response, supporting the view that the recovery of indoles over time is related to the extent of initial depletion, which in turn depends on critical drug brain concentrations. In view of the qualitative and quantitative species differences in the pharmacodynamics and pharmacokinetics of D-F neither of these rodent species is a suitable model for predicting potential drug toxicity in humans.