Neurotoxic effects of +/-fenfluramine and phenteramine, alone and in combination, on monoamine neurons in the mouse brain.

Until recently, (+/-)fenfluramine (FEN) was widely prescribed as an appetite suppressant. In animals, FEN is a potent and selective brain serotonin neurotoxin. The present studies assessed the effects of phentermine (PHEN), an appetite suppressant frequently used clinically in combination with FEN, on FEN-induced serotonin neurotoxicity. Groups (n = 6/group) of mice were treated with FEN (10 mg/kg), PHEN (20 mg/kg or 40 mg/kg), FEN (10 mg/kg) plus PHEN (20 mg/kg or 40 mg/kg), or vehicle twice daily for four days. Food intake and body weight were measured during and after drug treatment. Brains were evaluated for regional brain serotonin and dopamine axonal markers two weeks after drug treatment. PHEN enhanced the anorectic and weight-reducing effects of FEN. PHEN also significantly enhanced FEN's long-term toxic effects on 5-HT axons. This effect was evident in some (hypothalamus, striatum) but not all (hippocampus, cortex) brain regions examined. PHEN alone produced no long-term effects on 5-HT axonal markers. However, whether given alone or in combination with FEN, PHEN produced significant, dose-related decreases in striatal DA axonal markers. These results, coupled with those from previous studies, suggest that PHEN has the potential to exacerbate FEN-induced serotonin neurotoxicity, if utilized in certain doses. Further, the present results indicate that PHEN possesses dopamine (DA) neurotoxic potential. The relevance of these data to humans previously treated with FEN/PHEN is discussed.