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New evidence for a loss of serotonergic nerve terminals in rats treated with d,l-fenfluramine
1Clinical Research Centre, Royal Brisbane Hospital Foundation, Herston, Australia.
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 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.
Insights
Fenfluramine, an anorectic, may destroy serotonergic nerve terminals, unlike other agents that only block serotonin (5-HT) uptake sites. This study investigated fenfluramine
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- Fenfluramine is classified as a neurotoxin due to observed losses in serotonin (5-HT) uptake sites on nerve terminals.
- The exact mechanism, whether terminal destruction or reversible site blockade, remained unclear.
Purpose of the Study:
- To differentiate between the neurotoxic destruction of serotonergic terminals and the reversible blockade of 5-HT uptake sites by fenfluramine.
- To elucidate the mechanism underlying fenfluramine-induced changes in 5-HT uptake sites.
Main Methods:
- An animal model using male Wistar rats was established.
- Rats were injected with an irreversible 5-HT uptake site antagonist (EEDQ) to model reversible blockade.
- Fenfluramine and EEDQ effects on [3H]paroxetine binding and [14C]5-HT uptake/loading in synaptosomes were compared.
Main Results:
- EEDQ treatment resulted in reduced [3H]paroxetine binding and [14C]5-HT uptake, but not maximal [14C]5-HT loading, indicating reversible blockade.
- Fenfluramine treatment significantly reduced [3H]paroxetine binding, [14C]5-HT uptake, and maximal [14C]5-HT loading.
- Reduced maximal [14C]5-HT loading in fenfluramine-treated rats suggests irreversible damage to terminals.
Conclusions:
- Fenfluramine causes the destruction of serotonergic nerve terminals, supporting its classification as a neurotoxin.
- The findings distinguish fenfluramine's mechanism from agents that only inhibit 5-HT uptake sites.
- This research clarifies the neurotoxic potential of fenfluramine on the serotonergic system.