New Evidence for a Loss of Serotonergic Nerve Terminals in Rats Treated with d,l-Fenfluramine |
| |
Authors: | Robert I Westphalen Peter R Dodd |
| |
Abstract: | Abstract: 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 B max 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 (α) 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. |
| |
Keywords: | |
|
|