Original Article

Neuropsychopharmacology (2014) 39, 1355–1365; doi:10.1038/npp.2013.331; published online 5 February 2014

Evidence for a Role of Transporter-Mediated Currents in the Depletion of Brain Serotonin Induced by Serotonin Transporter Substrates

Michael H Baumann1, Simon Bulling2, Tova S Benaderet1, Kusumika Saha2, Mario A Ayestas1, John S Partilla1, Syed F Ali3, Thomas Stockner2, Richard B Rothman1, Walter Sandtner2 and Harald H Sitte2

  1. 1Medicinal Chemistry Section, Intramural Research Program (IRP), NIDA, NIH, Baltimore, MD, USA
  2. 2Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University Vienna, Vienna, Austria
  3. 3Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research (NCTR), FDA, Jefferson, AR, USA

Correspondence: Professor HH Sitte, Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University Vienna, Waehringerstrasse 13 A, Vienna 1090, Austria, Tel: +43 1 40160 31323, Fax: +43 1 40160 931300, E-mail: harald.sitte@meduniwien.ac.at

Received 31 May 2013; Revised 25 October 2013; Accepted 16 November 2013
Accepted article preview online 28 November 2013; Advance online publication 5 February 2014



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 [3H]5-HT in rat brain synaptosomes and transporter-mediated ionic currents in SERT-expressing Xenopus oocytes. When administered repeatedly to rats (6mg/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 [3H]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.


serotonin (5-HT) release; 5-HT depletion; 5-HT transporter (SERT); SERT substrate; SERT-mediated current

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