(+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters.
(+/-)-Fenfluramine is an amphetamine analog that was once widely prescribed as an appetite suppressant. Although (+/-)-fenfluramine is no longer clinically available, the mechanisms underlying its anorectic properties are still of interest. Upon peripheral administration, stereoisomers of (+/-)-fenfluramine are N-deethylated to form the metabolites, (+)- and (-)-norfenfluramine. It is well accepted that isomers of (+/-)-fenfluramine and (+/-)-norfenfluramine interact with 5-hydroxytryptamine (serotonin, 5-HT) transporters to release 5-HT from neurons. However, the effects of these drugs on other monoamine transporters are not well characterized. In this study, we examined the interaction of stereoisomers of (+/-)-fenfluramine and (+/-)-norfenfluramine with transporters for 5-HT, norepinephrine (NE), and dopamine (DA). Results from in vitro assays confirmed these drugs are potent substrates for 5-HT transporters: (+)-fenfluramine, (-)-fenfluramine, (+)-norfenfluramine, and (-)-norfenfluramine released [3H]5-HT from synaptosomes with EC50 values of 52, 147, 59, and 287 nM, respectively. Importantly, (+)-fenfluramine and (+)-norfenfluramine released [3H]NE with EC50 values of 302 and 73 nM. Results from in vivo microdialysis experiments showed that intravenous injection of (+)-norfenfluramine elevates extracellular levels of 5-HT, NE, and DA in rat frontal cortex. The effects of (+)-norfenfluramine on NE and DA were antagonized by pretreatment with the NE uptake blocker nisoxetine. In summary, administration of fenfluramines can increase synaptic levels of 5-HT, NE, and DA in the cortex, and (+)-norfenfluramine likely contributes to these effects. Release of NE and DA evoked by (+)-norfenfluramine is at least partly mediated via NE transporters. Our results emphasize the potential involvement of noradrenergic mechanisms in the actions of fenfluramines.
Rothman
Richard B
RB
Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Dr., P.O. Box 5180, Baltimore, MD 21224, USA. rrothman@intra.nida.nih.gov
Clark
Robert D
RD
Partilla
John S
JS
Baumann
Michael H
MH
D000818:Animals; D015306:Biogenic Monoamines / Q000032:analysis; D005277:Fenfluramine / Q000494:pharmacology*; D008297:Male; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009642:Norfenfluramine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D027981:Symporters / Q000187:drug effects / Q000378:metabolism*; D014316:Tritium
D015306:Biogenic Monoamines; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; D027981:Symporters; D014316:Tritium; D009642:Norfenfluramine; D005277:Fenfluramine; D012701:Serotonin