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NEUROPHARMACOLOGY

(+)-Fenfluramine and Its Major Metabolite, (+)-Norfenfluramine, Are Potent Substrates for Norepinephrine Transporters

Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland

(±)-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.

Address correspondence to: Dr. Richard B. Rothman, 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. E-mail: rrothman{at}intra.nida.nih.gov

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