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 x 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 microg; 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.
Department of Neurology, The Johns Hopkins Medical Institutions, 5001 Hopkins Bayview Circle, Baltimore, MD 21224, USA.
B T
BT
Callahan
B J
BJ
Cord
G A
GA
Ricaurte
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects* / Q000502:physiology; D001369:Axons / Q000187:drug effects* / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D005277:Fenfluramine / Q000633:toxicity*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D009434:Neural Pathways / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D010293:Pargyline / Q000494:pharmacology; D011392:Proline / Q000494:pharmacology; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000633:toxicity*; D017367:Selective Serotonin Reuptake Inhibitors / Q000633:toxicity*; D013997:Time Factors; D014316:Tritium / Q000494:pharmacology
D015116:5,7-Dihydroxytryptamine; D018759:Adrenergic Uptake Inhibitors; D003891:Desipramine; D005277:Fenfluramine; D006897:Hydroxyindoleacetic Acid; D008996:Monoamine Oxidase Inhibitors; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D009498:Neurotoxins; D010293:Pargyline; D011392:Proline; D012701:Serotonin; D018490:Serotonin Agents; D017367:Selective Serotonin Reuptake Inhibitors; D014316:Tritium