DIFFERENTIAL-EFFECTS OF D-FENFLURAMINE AND PARA-CHLOROAMPHETAMINE ON H75/12-INDUCED DEPLETION OF 5-HYDROXYTRYPTAMINE AND DOPAMINE IN THE RAT-BRAIN

The effects of the two 5-HT-releasing drugs, p-chloroamphetamine and d-fenfluramine, on central serotoninergic and dopaminergic systems were compared in adult rats. Both drugs (0.5-5.0 mg/kg i.p., 2 hr before death) produced a dose-dependent reduction in levels of 5-HT, but only p-chloroamphetamine decreased the levels of 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus, striatum and cerebral cortex. Within the dose range tested, d-fenfluramine did not affect the levels of DA and of its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in brain. By contrast, p-chloroamphetamine significantly increased the levels of DA and HVA and decreased the levels of DOPAC, notably in the straitum. As expected of a 5-HT uptake inhibitor, d-fenfluramine at small doses (0.2-0.5 mg/kg) prevented the depletion of 5-HT due to 4-methyl-alpha-ethyl-meta-tyramine (H75/12, 40 mg/kg i.p.), whereas at large doses (1.0-5.0 mg/kg) d-fenfluramine, like p-chloroamphetamine (0.2-1.0 mg/kg), slightly enhanced the effect of H75/12. Neither d-fenfluramine (0.5 mg/kg) nor p-chloroamphetamine (0.5 mg/kg) affect the depletion of DA due to H75/12. These data indicate that p-chloroamphetamine is a 5-HT-releasing drug, at any dose between 0.2 and 5.0 mg/kg, whereas d-fenfluramine acts as a 5-HT uptake inhibitor at 0.2-0.5 mg/kg and as a 5-HT releasing drug at larger doses. On account of the potential neurotoxicity of 5-HT-releasing drugs but not 5-HT uptake inhibitors, it can be inferred that d-fenfluramine is very probably devoid of any neurotoxic action in the dose range (< 1.0 mg/kg) required for its anorectic action.