Evidence for noncompetitive modulation of substrate-induced serotonin release

Synapse. 2010 Nov;64(11):862-9. doi: 10.1002/syn.20804.


Prior work indicated that serotonin transporter (SERT) inhibitors competitively inhibit substrate-induced [(3)H]5-HT release, producing rightward shifts in the substrate-dose response curve and increasing the EC(50) value without altering the E(max). We hypothesized that this finding would not generalize across a number of SERT inhibitors and substrates, and that the functional dissociation constant (Ke) of a given SERT inhibitor would not be the same for all tested substrates. To test this hypothesis, we utilized a well-characterized [(3)H]5-HT release assay that measures the ability of a SERT substrate to release preloaded [(3)H]5-HT from rat brain synaptosomes. Dose-response curves were generated for six substrates (PAL-287 [naphthylisopropylamine], (+)-fenfluramine, (+)-norfenfluramine, mCPP [meta-chlorophenylpiperazine], (±)-MDMA, 5-HT) in the absence and presence of a fixed concentration of three SERT inhibitors (indatraline, BW723C86, EG-1-149 [4-(2-(benzhydryloxy)ethyl)-1-(4-bromobenzyl)piperidine oxalate]). Consistent with simple competitive inhibition, all SERT inhibitors increased the EC(50) value of all substrates. However, in many cases a SERT inhibitor decreased the E(max) value as well, indicating that in the presence of the SERT inhibitor the substrate became a partial releaser. Moreover, the Ke values of a given SERT inhibitor differed among the six SERT substrates, indicating that each inhibitor/substrate combination had a unique interaction with the transporter. Viewed collectively, these findings suggest that it may be possible to design SERT inhibitors that differentially regulate SERT function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / ultrastructure
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • In Vitro Techniques
  • Indoles / pharmacology
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Serotonin / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Serotonin Receptor Agonists / pharmacology
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism
  • Thiophenes / pharmacology
  • Time Factors
  • Tritium / metabolism


  • 1-(5-(2-thenyloxy)-1H-indol-3-yl)propan-2-amine
  • Indoles
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Receptor Agonists
  • Serotonin Uptake Inhibitors
  • Thiophenes
  • Tritium
  • Serotonin