Using the 5‐HT Transporter Dependency of p‐Chloroamphetamine‐Stimulated 5‐HT Release to Determine the Nature of Fenfluramine‐Induced 5‐HT Transporter Loss

The amphetamine derivatives p-chloroamphetamine (pCA), fenfluramine, 3,4methylenedioxyamphetamine (MDA), and 3,4-methylenedioxymethamphetamine (MDMA), selectively release serotonin (5-HT) from serotonergic nerve terminals in a dose-dependent manner.' Compounds that bind to the presynaptic 5-HT transporter and inhibit 5-HT reuptake also block the releasing affects of these substituted amphetamines,* indicating that the mechanism of release is mediated through the neuronal5-HT transport system. Administering substituted amphetamines to laboratory animals results in the long-term manifestation of two indicators of serotonergic nerve injury: depletion of brain serotonin3 and reductions in 5-HT transporter d e n ~ i t y . ~ Since these markers of 5-HT-containing nerve terminals are reduced long after the drug or its metabolites are removed from brain, it has been concluded that the administration of substituted amphetamines causes serotonergic neuro to~ic i ty .~-~ However, unlike the other amphetamine derivatives, fenfluramine does not generate other indices of neurological damage, such as morphological changes6 and a s t r o g l i ~ s i s . ~ ~ ~ Therefore, the question of whether fenfluramine reduces 5-HT transporters by destroying serotonergic nerve terminals, or rather, downregulates 5-HT transporter density, remains pertinent. In this study, the need for pCA to be transported into 5-HT-containing nerve endings before it can initiate 5-HT release was used to distinguish serotonergic nerve terminal loss from a loss of 5-HT transporters on otherwise intact 5-HT containing terminals.