New evidence for a loss of serotonergic nerve terminals in rats treated with d,l-fenfluramine.
Fenfluramine has been classified as a neurotoxin because animals treated with this anorectic lose 5-HT uptake sites located on serotonergic nerve terminals. However, there are two possible bases for this finding: either uptake sites are lost because the terminals themselves have been destroyed (neurotoxicity); or uptake sites are lost from otherwise intact terminals. To distinguish between these possibilities, we established an animal model in which male Wistar rats were injected (intraperitoneally) with an irreversible 5-HT uptake site antagonist (EEDQ). Since their 5-HT sites were inhibited (blocked) non-competitively, by this agent, such animals had effectively lost 5-HT uptake sites from intact serotonergic terminals. Synaptosomes prepared from such animals showed the predicted reduction in the Bmax of [3H]paroxetine binding to the 5-HT uptake site, and a reduction in the Vmax of [14C]5-HT uptake. However, they showed no significant reduction in maximal [14C]5-HT loading (alpha) compared with synaptosome from sham-injected controls. In contrast, fenfluramine-treated animals showed reduced [3H]paroxetine binding, reduced maximal [14C]5-HT uptake and significantly (P < 0.02) reduced synaptosomal [14C]5-HT loading. Therefore, the results suggest that fenfluramine does indeed cause the destruction of serotonergic nerve terminals.
Clinical Research Centre, Royal Brisbane Hospital Foundation, Herston, Australia.
R I
RI
Westphalen
P R
PR
Dodd
D000818:Animals; D001921:Brain / Q000187:drug effects*; D005277:Fenfluramine / Q000494:pharmacology*; D008297:Male; D009411:Nerve Endings / Q000187:drug effects* / Q000378:metabolism; D017374:Paroxetine / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists; D013237:Stereoisomerism; D013570:Synaptic Membranes / Q000378:metabolism
D011804:Quinolines; D012702:Serotonin Antagonists; D005277:Fenfluramine; D012701:Serotonin; D017374:Paroxetine; C000470:EEDQ