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.