REPEATED ADMINISTRATION OF ESCALATING HIGH-DOSES OF DEXFENFLURAMINE DOES NOT PRODUCE MORPHOLOGICAL EVIDENCE FOR NEUROTOXICITY IN THE CORTEXOF RATS

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 recei ved vehicle and were allowed food ad libitum or were pair fed with dex fenfluramine-treated animals. Immediately following drug treatment 5-H T 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 re covered to control values by 15 days. GFAP and GAP 43 immunoreactivity was unaffected by dexfenfluramine treatment compared to control anima ls, indicating a lack of evidence for neuronal degeneration and regene ration. Dexfenfluramine treatment decreased the density of 5-HT uptake sites in the cortex, labelled with [H-3]-citalopram, but this partial ly recovered towards control values at 60 days. These alterations in 5 -HT terminal networks conflict with the return of 5-HT levels to norma l and the lack of evidence for degenerative changes or neuronal regrow th. On the basis of these results, it cannot be concluded that dexfenf luramine is neurotoxic. (C) 1996 Academic Press Limited.