R. Lew et al., COMBINED PHENTERMINE FENFLURAMINE ADMINISTRATION ENHANCES DEPLETION OF SEROTONIN FROM CENTRAL TERMINAL FIELDS/, Synapse, 26(1), 1997, pp. 36-45
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 to
gether for weight reduction. Repeated administration of Fen is known t
o cause long-term depletion of axonal serotonin (5-HT) and loss of 5-H
T 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. Comb
ined administration of Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.12
5 mg/kg) caused significantly greater reductions of 5-HT levels in the
striatum, nucleus accumbens/olfactory tubercle, hypothalamus, amygdal
a, frontal parietal cortex, and hippocampus than either drug alone. Co
mbined 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 st
riatum 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/k
g/3.125 mg/kg) caused greater weight loss than that observed with eith
er compound alone. Collectively, the present data demonstrate that com
bined Phen/Fen administration enhances the neurotoxicity of Phen or Fe
n on 5-HT neurons. (C) 1997 Wiley-Liss, Inc.