EFFECTS OF PHENTERMINE AND COCAINE ON FENFLURAMINE-INDUCED DEPLETION OF SEROTONIN IN MOUSE-BRAIN

The combined administration of phentermine and fenfluramine (PHEN/FEN) has been used as a treatment for obesity. Recent evidence suggests th at this drug mixture may also be an effective medication for substance abuse disorders, including cocaine dependence. It is well-established that repeated high-dose fenfluramine causes serotonin (5-HT) terminal degeneration in laboratory animals, and no studies have addressed pos sible interactions between phentermine and fenfluramine. The purpose o f the present work was to examine the effect of phentermine coadminist ration on fenfluramine-induced depletion of 5-HT in mouse forebrain. I n addition, because of the potential for cocaine abuse in drug addicts taking PHEN/FEN as a medication, we examined the effects of PHEN/FEN on forebrain 5-HT levels in the presence or absence of cocaine. Fenflu ramine (0, 3, 10, 30 mg/kg, s.c. twice daily for 4 days) caused a dose -dependent reduction in forebrain 5-HT without affecting dopamine or n orepinephrine. Phentermine coadministration (7 mg/kg, s.c. twice daily for 4 days) did not significantly alter the 5-HT-depleting effect of fenfluramine. Likewise, cocaine (10 mg/kg, i.p.), administered 60 min prior to or 60 min after PHEN/FEN, had no effect on the PHEN/FEN-induc ed decrease in central 5-HT. The present results indicate that doses o f phentermine far above those typically administered to humans do not potentiate the 5-HT-depleting effect of repeated high-dose fenfluramin e. Moreover, exposure to cocaine does not significantly alter the long -term neurochemical actions of the PHEN/FEN mixture.