Long-term impairment of anterograde axonal transport along fiber projections originating in the rostral raphe nuclei after treatment with fenfluramine or methylenedioxymethamphetamine

To further evaluate the serotonin (5-HT) neurotoxic potential of substituted amphetamines, we used tritiated proline to examine anterograde transport along ascending axonal projections originating in the rostral raphe nuclei of animals treated 3 weeks previously with (±)fenfluramine (FEN, 10 mg/kg, every 2 h × 4 injections; i.p.) or (±)3,4-methylenedioxymethamphetamine (MDMA, 20 mg/kg, twice daily for 4 days; s.c.). The documented 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT, 75 μg; ICV; 30 min after pretreatment with pargyline, 50 mg/kg; i.p., and desipramine 25 mg/kg; i.p.), served as a positive control. Along with anterograde axonal transport, we measured two 5-HT axonal markers, 5-HT and 5-hydroxyindoleacetic acid (5-HIAA). Prior treatment with FEN or MDMA led to marked reductions in anterograde transport of labeled material to various forebrain regions known to receive 5-HT innervation. These reductions were associated with lasting decrements in 5-HT axonal markers. In general, decreases in axonal transport were less pronounced than those in 5-HT and 5-HIAA. However, identical changes were observed after 5,7-DHT. These results further indicate that FEN and MDMA, like 5,7-DHT, are 5-HT neurotoxins.