title: Serotonin-transporter mediated efflux: a pharmacological analysis of amphetamines and non-amphetamines.
abstract: The physiological function of neurotransmitter transporter proteins like the serotonin transporter (SERT) is reuptake of neurotransmitter that terminates synaptic serotoninergic transmission. SERT can operate in reverse direction and be induced by SERT substrates including 5-HT, tyramine and the positively charged methyl-phenylpyridinium (MPP(+)), as well as the amphetamine derivatives para-chloroamphetamine (pCA) and methylene-dioxy-methamphetamine (MDMA). These substrates also induce inwardly directed sodium currents that are predominantly carried by sodium ions. Efflux via SERT depends on this sodium flux that is believed to be a prerequisite for outward transport. However, in recent studies, it has been suggested that substrates may be distinct in their properties to induce efflux. Therefore, the aim of the present study was a pharmacological characterization of different SERT substrates in uptake experiments, their abilities to induce transporter-mediated efflux and currents. In conclusion, the rank order of affinities in uptake and electrophysiological experiments correlate well, while the potencies of the amphetamine derivatives for the induction of efflux are clearly higher than those of the other substrates. These discrepancies can be only explained by mechanisms that can be induced by amphetamines. Therefore, based on our pharmacological observations, we conclude that amphetamines distinctly differ from non-amphetamine SERT substrates.
authors.affiliation: Institute of Pharmacology, Medical University Vienna, Waehringerstr. 13a, A-1090 Vienna, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Hilber
authors.forename: Petra
authors.initials: P
authors.lastname: Scholze
authors.forename: Mario M
authors.initials: MM
authors.lastname: Dorostkar
authors.forename: Walter
authors.initials: W
authors.lastname: Sandtner
authors.forename: Marion
authors.initials: M
authors.lastname: Holy
authors.forename: Stefan
authors.initials: S
authors.lastname: Boehm
authors.forename: Ernst A
authors.initials: EA
authors.lastname: Singer
authors.forename: Harald H
authors.initials: HH
authors.lastname: Sitte
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014316:Tritium / Q000493:pharmacokinetics; D014439:Tyramine / Q000493:pharmacokinetics
chemical_list: D000661:Amphetamine; D018765:Dopamine Uptake Inhibitors; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D012701:Serotonin; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014316:Tritium; D014439:Tyramine