The nature of d,l-fenfluramine-induced 5-HT reuptake transporter loss in rats.
The administration of the anorexigenic drug d,l-fenfluramine (Ponderax) to laboratory animals results in a dose-dependent reduction in presynaptically located serotonergic reuptake transporter protein. This long-term effect may represent an altered mechanism of synthesis of the transporter (downregulation). Alternatively, fenfluramine may destroy the serotonergic terminals on which 5-HT transporters are located. To distinguish between these two alternatives, we applied an assay of neurotransmitter-specific nerve endings (alpha) to brain tissue from two animal models of reduced 5-HT transporter density. In Model 1, serotonergic nerve terminals were destroyed (rats received 5,7-dihydroxytryptamine [5,7-DHT] intracisternally); in Model 2, there was a loss of 5-HT transporter per se on otherwise intact serotonergic nerve terminals. The manner in which alpha declined as transporter density was decreased (reducing Vmax values) in animal Models 1 and 2 was found to be significantly different. In rats treated with fenfluramine, the association between 5-HT transporter density and alpha was the same as in the neurotoxic model.
Westphalen
R I
RI
Clinical Research Centre, Royal Brisbane Hospital Foundation, Bancroft Centre, Australia.
Dodd
P R
PR
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005277:Fenfluramine / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000378:metabolism; D026901:Membrane Transport Proteins; D008959:Models, Neurological; D009419:Nerve Tissue Proteins; D009498:Neurotoxins / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism
D015116:5,7-Dihydroxytryptamine; D002352:Carrier Proteins; D005277:Fenfluramine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D011804:Quinolines; D012701:Serotonin; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493232:Slc6a4 protein, rat; C000470:EEDQ