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

Abstract

(Ϯ)-Fenfluramine is an amphetamine analog that was once widely prescribed as an appetite suppressant. Although (Ϯ)-fenfluramine is no longer clinically available, the mechanisms underlying its anorectic properties are still of interest. Upon peripheral administration, stereoisomers of (Ϯ)-fenfluramine are N-deethylated to form the metabolites, (ϩ)-and (Ϫ)-norfenfluramine. It is well accepted that isomers of (Ϯ)-fenfluramine and (Ϯ)-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 (Ϯ) Results from in vivo microdialysis experiments showed that intravenous injection of (ϩ)-norfenfluramine elevates extracellular levels of 5-HT, NE, and DA in rat frontal cortex. The effects of (ϩ)-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 (ϩ)-norfenfluramine likely contributes to these effects. Release of NE and DA evoked by (ϩ)-norfenfluramine is at least partly mediated via NE transporters. Our results emphasize the potential involvement of noradrenergic mechanisms in the actions of fenfluramines.

The serotonin releaser fenfluramine alters the auditory responses of inferior colliculus neurons

“…Fenfluramine and serotonin-Although the effects of fenfluramine are quite similar to those previously reported for iontophoresed serotonin (Hurley and Pollak 2001), fenfluramine also releases norepinephrine at a lower affinity than serotonin (Rowland and Carlton 1986;Rothman et al 2003). In order to determine whether the effects of fenfluramine are mediated by serotonin, we directly compared the effects of fenfluramine and serotonin in 20 neurons.…”

“…Neurons with divergent effects of fenfluramine and serotonin were in the minority, but for these neurons it is possible that fenfluramine had effects other than the release of serotonin. In addition to releasing serotonin, fenfluramine can trigger the release of norepinephrine, although at a lower efficacy, and may also alter dopamine release through direct or indirect mechanisms (Rowland and Carlton 1986;Rothman et al 2003). Thus, for the small number of neurons in which the effects of fenfluramine and serotonin did not coincide, it is possible that the divergent effects were due to fenfluramine-evoked release of another signaling molecule instead of, or in addition to, the release of serotonin.…”

“…Fenfluramine is an amphetamine derivative with selectivity for the serotonergic system that in the short term increases serotonin levels in the brain but over the course of days or weeks may deplete serotonin (Rowland and Carlton 1986;Schwartz et al 1989;Baumann et al 2000;Tao et al 2002;Rothman et al 2003;Itzhak and Ali 2006). This study focuses on the effects of iontophoretically applied fenfluramine on the auditory responses of single IC neurons in a time frame of minutes.…”

Therapeutic Potential of Monoamine Transporter Substrates

“…a The functional endpoint of these data is phosphoinositide hydrolysis [73] . b From [42]. c From [40].…”

“…This work served to identify the mechanism of action of known stimulant-type agents [40][41][42][43] and to guide the synthesis and evaluation of novel treatment agents for addictive disorders [21]. Traditionally, it has been difficult to use simple test tube assays to discriminate between drugs that are uptake inhibitors vs. those that are substrate-type releasers [8,11].…”