title: Repeated administration of escalating high doses of dexfenfluramine does not produce morphological evidence for neurotoxicity in the cortex of rats.
abstract: Rats were treated for 28 days with increasing doses of dexfenfluramine (0.5, 1, 1.5, 2, 3, 4 and 5 mg/kg bid ip, each dose given for 4 days before being increased) and subsequently studied at intervals between 1 and 60 days following the cessation of treatment. Control rats received vehicle and were allowed food ad libitum or were pair fed with dexfenfluramine-treated animals. Immediately following drug treatment 5-HT immunoreactivity was increased in cortical areas compared to control animals. Subsequently, there was a persistent decrease in fine fibre density and the appearance of coarse truncated fibres. 5-HT levels in cortex were decreased 1 day following dexfenfluramine treatment but recovered to control values by 15 days. GFAP and GAP 43 immunoreactivity was unaffected by dexfenfluramine treatment compared to control animals, indicating a lack of evidence for neuronal degeneration and regeneration. Dexfenfluramine treatment decreased the density of 5-HT uptake sites in the cortex, labelled with [3H]-citalopram, but this partially recovered towards control values at 60 days. These alterations in 5-HT terminal networks conflict with the return of 5-HT levels to normal and the lack of evidence for degenerative changes or neuronal regrowth. On the basis of these results, it cannot be concluded that dexfenfluramine is neurotoxic.
authors.affiliation: Neurodegenerative Diseases Research Centre, King's College London.
authors.forename: S
authors.initials: S
authors.lastname: Rose
authors.forename: S
authors.initials: S
authors.lastname: Hunt
authors.forename: P
authors.initials: P
authors.lastname: Collins
authors.forename: J G
authors.initials: JG
authors.lastname: Hindmarsh
authors.forename: P
authors.initials: P
authors.lastname: Jenner
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000633:toxicity*; D001665:Binding Sites; D015415:Biomarkers; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D015283:Citalopram / Q000378:metabolism; D005277:Fenfluramine / Q000633:toxicity*; D019922:GAP-43 Protein; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D009410:Nerve Degeneration; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D009416:Nerve Regeneration; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009498:Neurotoxins; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*
chemical_list: D001067:Appetite Depressants; D015415:Biomarkers; D019922:GAP-43 Protein; D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D015283:Citalopram; D005277:Fenfluramine; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid