title: Evidence for a role of transporter-mediated currents in the depletion of brain serotonin induced by serotonin transporter substrates.
abstract: Serotonin (5-HT) transporter (SERT) substrates like fenfluramine and 3,4-methylenedioxymethamphetamine cause long-term depletion of brain 5-HT, while certain other substrates do not. The 5-HT deficits produced by SERT substrates are dependent upon transporter proteins, but the exact mechanisms responsible are unclear. Here, we compared the pharmacology of several SERT substrates: fenfluramine, d-fenfluramine, 1-(m-chlorophenyl)piperazine (mCPP) and 1-(m-trifluoromethylphenyl)piperainze (TFMPP), to establish relationships between acute drug mechanisms and the propensity for long-term 5-HT depletions. In vivo microdialysis was carried out in rat nucleus accumbens to examine acute 5-HT release and long-term depletion in the same subjects. In vitro assays were performed to measure efflux of [(3)H]5-HT in rat brain synaptosomes and transporter-mediated ionic currents in SERT-expressing Xenopus oocytes. When administered repeatedly to rats (6 mg/kg, i.p., four doses), all drugs produce large sustained elevations in extracellular 5-HT (>5-fold) with minimal effects on dopamine. Importantly, 2 weeks after dosing, only rats exposed to fenfluramine and d-fenfluramine display depletion of brain 5-HT. All test drugs evoke fluoxetine-sensitive efflux of [(3)H]5-HT from synaptosomes, but d-fenfluramine and its bioactive metabolite d-norfenfluramine induce significantly greater SERT-mediated currents than phenylpiperazines. Our data confirm that drug-induced 5-HT release probably does not mediate 5-HT depletion. However, the magnitude of transporter-mediated inward current may be a critical factor in the cascade of events leading to 5-HT deficits. This hypothesis warrants further study, especially given the growing popularity of designer drugs that target SERT.
authors.affiliation: Medicinal Chemistry Section, Intramural Research Program (IRP), NIDA, NIH, Baltimore, MD, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
authors.affiliation: Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University Vienna, Vienna, Austria.
authors.forename: Simon
authors.initials: S
authors.lastname: Bulling
authors.affiliation: Medicinal Chemistry Section, Intramural Research Program (IRP), NIDA, NIH, Baltimore, MD, USA.
authors.forename: Tova S
authors.initials: TS
authors.lastname: Benaderet
authors.affiliation: Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University Vienna, Vienna, Austria.
authors.forename: Kusumika
authors.initials: K
authors.lastname: Saha
authors.affiliation: Medicinal Chemistry Section, Intramural Research Program (IRP), NIDA, NIH, Baltimore, MD, USA.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Ayestas
authors.affiliation: Medicinal Chemistry Section, Intramural Research Program (IRP), NIDA, NIH, Baltimore, MD, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Partilla
authors.affiliation: Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research (NCTR), FDA, Jefferson, AR, USA.
authors.forename: Syed F
authors.initials: SF
authors.lastname: Ali
authors.affiliation: Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stockner
authors.affiliation: Medicinal Chemistry Section, Intramural Research Program (IRP), NIDA, NIH, Baltimore, MD, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.affiliation: Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University Vienna, Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Sandtner
authors.affiliation: Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University Vienna, Vienna, Austria.
authors.forename: Harald H
authors.initials: HH
authors.lastname: Sitte
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D005277:Fenfluramine / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014982:Xenopus laevis
chemical_list: D010879:Piperazines; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; C018406:1-(3-trifluoromethylphenyl)piperazine; D005277:Fenfluramine; D012701:Serotonin; C015068:1-(3-chlorophenyl)piperazine; D004298:Dopamine