Combined phentermine/fenfluramine administration enhances depletion of serotonin from central terminal fields

Administration of phentermine (Phen) together with (+/-) fenfluramine (Fen) enhances the weight reduction that is observed with either drug alone; consequently, these anorectic agents are commonly prescribed together for weight reduction. Repeated administration of Fen is known to cause long-term depletion of axonal serotonin (5-HT) and loss of 5-HT transporters, and is therefore considered neurotoxic. We now report that combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg, and 20 mg/kg/3.125 mg/kg) can enhance the neurotoxic effect of Fen (3.125 mg/kg) and Phen (5 mg/kg and 20 mg/kg) on central 5-HT systems. Rats were repeatedly treated once each hour for a total of four injections with saline, Phen (5 mg/kg and 20 mg/kg), Fen (3.125 mg/kg and 12.5 mg/kg), or combined Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg), and sacrificed either 7 or 28 days after cessation of treatment. Combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg) caused significantly greater reductions of 5-HT levels in the striatum, nucleus accumbens/olfactory tubercle, hypothalamus, amygdala, frontal parietal cortex, and hippocampus than either drug alone. Combined Phen/Fen at the higher drug-dose combination (20 mg/kg/3.125 mg/kg) was observed to reduce the density of 5-HT transporters in rat striatum at both 7 and 28 days after cessation of treatment. In addition, combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg) caused greater weight loss than that observed with either compound alone. Collectively, the present data demonstrate that combined Phen/Fen administration enhances the neurotoxicity of Phen or Fen on 5-HT neurons.