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Sensory Perception pp 183–203Cite as

Towards an understanding of the psychostimulant action of amphetamine and cocaine

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Abstract

Cocaine and amphetamine are psychostimulant drugs that are illicitly used; they affect sensory perception by targeting the neurotransmitter: sodium symporters (NSS) at the synapses between neurons. They both increase the concentration of the neurotransmitter in the synaptic cleft but by different means.

The physiological role of NSS is the reuptake of their endogenous substrate. For this task, they exploit the pre-existing sodium-gradient across the cellular membrane that is maintained by the activity of the sodium:potassium pump. This reuptake process terminates synaptic transmission because the neurotransmitter is removed from the synaptic cleft — and its action on pre- and postsynaptic receptor molecules is stopped.

Amphetamines induce the reverse operation of distinct NSS family members, whereas cocaine merely inhibits the same transporters and thereby blocks the reuptake of neurotransmitter. These effects, although completely different in molecular mechanism, lead to an increase in the synaptic concentration of non-exocytotically released neurotransmitters. While these actions have long been appreciated, the underlying mechanistic details have been surprisingly difficult to understand. The advent of a crystal structure of a prokaryotic NSS protein and the concomitant development of homology models for eukaryotic NSS family members generated novel insights into the structure-function relationships of this clinically relevant class of transporters. Ultimately, we hope to understand the effects of amphetamines and cocaine on a molecular level to elucidate their profound effects on sensory perception.

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References

  • Amara SG, Kuhar MJ (1993) Neurotransmitter transporters: recent progress. Annu Rev Neurosci 16: 73–93

    Article  PubMed  CAS  Google Scholar 

  • Amara SG, Sonders MS (1998) Neurotransmitter transporters as molecular targets for addictive drugs. Drug Alcohol Depend 51: 87–96

    Article  PubMed  CAS  Google Scholar 

  • Axelrod J, Whitby LG, Hertting G (1961) Effect of psychotropic drugs on the uptake of 3H-Norepinephrine by tissues. Science 133: 383–384

    Article  PubMed  CAS  Google Scholar 

  • Beuming T, Kniazeff J, Bergmann ML, Shi L, Gracia L, Raniszewska K, Newman AH, Javitch JA, Weinstein H, Gether U, Loland CJ (2008) The binding sites for cocaine and dopamine in the dopamine transporter overlap. Nat Neurosci 11: 780–789

    Article  PubMed  CAS  Google Scholar 

  • Beuming T, Shi L, Javitch JA, Weinstein H (2006) A comprehensive structure-based alignment of prokaryotic and eukaryotic neurotransmitter/ Na+ symporters (NSS) aids in the use of the LeuT structure to probe NSS structure and function. Mol Pharmacol 70: 1630–1642

    Article  PubMed  CAS  Google Scholar 

  • Biel JH, Bopp BA (1978) Amphetamines: structure-activity relationships. In: Iversen LL, Iversen SD, Snyder SH (eds) Handbook of psychopharmacology: psychostimulants. pp 1–40, Plenum, New York

    Google Scholar 

  • Blakely RD, Berson HE, Fremeau-RTJ, Caron MG, Peek MM, Prince HK, Bradley CC (1991) Cloning and expression of a functional serotonin transporter from rat brain. Nature 354: 66–70

    Article  PubMed  CAS  Google Scholar 

  • Bönisch H (1984) The transport of (+)-amphetamine by the neuronal noradrenaline carrier. Naunyn Schmiedebergs Arch Pharmacol 327: 267–272

    Article  PubMed  Google Scholar 

  • Bönisch H (1986) The role of co-transported sodium in the effect of indirectly acting sympathomimetic amines. Naunyn Schmiedebergs Arch Pharmacol 332: 135–141

    Article  PubMed  Google Scholar 

  • Bönisch H, Trendelenburg U (1989) The mechanism of action of indirectly acting sympathomimetic amines. In: Trendelenburg U, Weiner N (eds) Handbook of Experimental Pharmacology: Catecholamines. pp 247–277, Springer, Berlin, Hamburg, New York

    Google Scholar 

  • Bruss M, Hammermann R, Brimijoin S, Bonisch H (1995) Antipeptide antibodies confirm the topology of the human norepinephrine transporter. J Biol Chem 270: 9197–9201

    Article  PubMed  CAS  Google Scholar 

  • Burn JH, Rand MJ (1958) The action of sympathomimetic amines in animals treated with reserpine. J Physiol 144: 314–336

    PubMed  CAS  Google Scholar 

  • Carvelli L, McDonald PW, Blakely RD, DeFelice LJ (2004) Dopamine transporters depolarize neurons by a channel mechanism. Proc Natl Acad Sci U S A 101: 16046–16051

    Article  PubMed  CAS  Google Scholar 

  • Chen N, Reith ME (2000) Structure and function of the dopamine transporter. Eur J Pharmacol 405: 329–339

    Article  PubMed  CAS  Google Scholar 

  • Chen R, Furman CA, Zhang M, Kim MN, Gereau RW, Leitges M, Gnegy ME (2009) Protein kinase Cbeta is a critical regulator of dopamine transporter trafficking and regulates the behavioral response to amphetamine in mice. J Pharmacol Exp Ther 328: 912–920

    Article  PubMed  CAS  Google Scholar 

  • Cinquanta M, Ratovitski T, Crespi D, Gobbi M, Mennini T, Simantov R (1997) Carrier-mediated serotonin release induced by d-fenfluramine: studies with human neuroblastoma cells transfected with a rat serotonin transporter. Neuropharmacology 36: 803–809

    Article  PubMed  CAS  Google Scholar 

  • Davis ME, Patrick RL (1990) Diacylglycerol-induced stimulation of neurotransmitter release from rat brain striatal synaptosomes. J Neurochem 54: 662–668

    Article  PubMed  CAS  Google Scholar 

  • Desai RI, Kopajtic TA, Koffarnus M, Newman AH, Katz JL (2005) Identification of a dopamine transporter ligand that blocks the stimulant effects of cocaine. J Neurosci 25: 1889–1893

    Article  PubMed  CAS  Google Scholar 

  • Egana LA, Cuevas RA, Baust TB, Parra LA, Leak RK, Hochendoner S, Pena K, Quiroz M, Hong WC, Dorostkar MM, Janz R, Sitte HH, Torres GE (2009) Physical and functional interaction between the dopamine transporter and the synaptic vesicle protein synaptogyrin-3. J Neurosci 29: 4592–4604

    Article  PubMed  CAS  Google Scholar 

  • Erreger K, Grewer C, Javitch JA, Galli A (2008) Currents in response to rapid concentration jumps of amphetamine uncover novel aspects of human dopamine transporter function. J Neurosci 28: 976–989

    Article  PubMed  CAS  Google Scholar 

  • Eshleman AJ, Henningsen RA, Neve KA, Janowsky A (1994) Release of dopamine via the human transporter. Mol Pharmacol 45: 312–316

    PubMed  CAS  Google Scholar 

  • Ewing AG, Stein TS, Lau YY (1992) Analytical chemistry in microenvironments: single nerve cells. Accts Chem Res 440–447

    Google Scholar 

  • Farhan H, Freissmuth M, Sitte HH (2006) Oligomerization of neurotransmitter transporters: a ticket from the endoplasmic reticulum to the plasma membrane. Handb Exp Pharmacol 233–249

    Google Scholar 

  • Farhan H, Korkhov VM, Paulitschke V, Dorostkar MM, Scholze P, Kudlacek O, Freissmuth M, Sitte HH (2004) two discontinuous segments in the carboxy terminus are required for membrane targeting of the rat GABA transporter-1 (GAT1). J Biol Chem 279: 28 553–28 563

    Article  CAS  Google Scholar 

  • Farhan H, Reiterer V, Korkhov VM, Schmid JA, Freissmuth M, Sitte HH (2007) concentrative export from the endoplasmic reticulum of the gamma-aminobutyric acid transporter 1 requires binding to SEC24D. J Biol Chem 282: 7679–7689

    Article  PubMed  CAS  Google Scholar 

  • Farhan H, Reiterer V, Kriz A, Hauri HP, Pavelka M, Sitte HH, Freissmuth M (2008) Signal-dependent export of GABA transporter 1 from the ER-golgi intermediate compartment is specified by a Cterminal motif. J Cell Sci 121: 753–761

    Article  PubMed  CAS  Google Scholar 

  • Fischer JF, Cho AK (1979) Chemical release of dopamine from striatal homogenates: evidence for an exchange diffusion model. J Pharmacol Exp Ther 208: 203–209

    PubMed  CAS  Google Scholar 

  • Fishkes H, Rudnick G (1982) Bioenergetics of serotonin transport by membrane vesicles derived from platelet dense granules. J Biol Chem 257: 5671–5677

    PubMed  CAS  Google Scholar 

  • Fjorback AW, Pla P, Muller HK, Wiborg O, Saudou F, Nyengaard JR (2009) Serotonin transporter oligomerization documented in rn46 a cells and neurons by sensitized acceptor emission FRET and fluorescence lifetime imaging microscopy. Biochem Biophys Res Commun 380: 724–728

    Article  PubMed  CAS  Google Scholar 

  • Fleckenstein A, Burn JH (1953) The effect of denervation on the action of sympathomimetic amines on the nictitating membrane. Br J Pharmacol Chemother 8: 69–78

    Article  PubMed  CAS  Google Scholar 

  • Fog JU, Khoshbouei H, Holy M, Owens WA, Vaegter CB, Sen N, Nikandrova Y, Bowton E, McMahon DG, Colbran R J, Daws L C, Sitte HH, Javitch JA, Galli A, Gether U (2006) Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport. Neuron 51: 417–429

    Article  PubMed  CAS  Google Scholar 

  • Forrest LR, Zhang YW, Jacobs MT, Gesmonde J, Xie L, Honig BH, Rudnick G (2008) Mechanism for alternating access in neurotransmitter transporters. Proc Natl Acad Sci USA 105: 10 338–10 343

    Article  CAS  Google Scholar 

  • Foster JD, Pananusorn B, Vaughan RA (2002) Dopamine transporters are phosphorylated on N-terminal serines in rat striatum. J Biol Chem 277: 25 178–25 186

    Article  CAS  Google Scholar 

  • Furchgott RF, Kirpekar SM, Rieker M, Schwab A (1963) Actions and interactions of norepinephrine, tyramine and cocaine on aortic strips of rabbit and left atria of guinea pig and cat. J Pharmacol Exp Ther 142: 39–58

    PubMed  CAS  Google Scholar 

  • Giambalvo CT (1992 a) Protein kinase C and dopamine transport-1. effects of amphetamine in vivo. Neuropharmacology 31: 1201–1210

    Article  PubMed  CAS  Google Scholar 

  • Giambalvo CT (1992 b) Protein kinase C and dopamine transport-2. effects of amphetamine in vitro. Neuropharmacology 31: 1211–1222

    Article  PubMed  CAS  Google Scholar 

  • Giambalvo CT (2003) Differential effects of amphetamine transport vs. dopamine reverse transport on particulate pkc activity in striatal synaptoneurosomes. Synapse 49: 125–133

    Article  PubMed  CAS  Google Scholar 

  • Giros B, el Mestikawy S, Bertrand L, Caron MG (1991) Cloning and functional characterization of a cocaine-sensitive dopamine transporter. FEBS Lett 295: 149–154

    Article  PubMed  CAS  Google Scholar 

  • Giros B, Jaber M, Jones SR, Wightman RM, Caron MG (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379: 606–612

    Article  PubMed  CAS  Google Scholar 

  • Glowinski J, Axelrod J (1965) Effect of drugs on the uptake, release, and metabolism of H3-norepinephrine in the rat brain. J Pharmacol Exp Ther 149: 43–49

    PubMed  CAS  Google Scholar 

  • Gnegy ME (2003) the effect of phosphorylation on amphetamine-mediated outward transport. Eur J Pharmacol 479: 83–91

    Article  PubMed  CAS  Google Scholar 

  • Gnegy ME, Khoshbouei H, Berg K A, Javitch JA, Clarke WP, Zhang M, Galli A (2004) Intracellular Ca2+ regulates amphetamine-induced dopamine efflux and currents mediated by the human dopamine transporter. Mol Pharmacol 66: 137–143

    Article  PubMed  CAS  Google Scholar 

  • Gobbi M, Funicello M, Gerstbrein K, Holy M, Moya PR, Sotomayor R, Forray MI, Gysling K, Paluzzi S, Bonanno G, Reyes-Parada M, Sitte HH, Mennini T (2008) N,N-dimethyl-thioamphetamine and methyl-thioamphetamine, two non-neurotoxic substrates of 5-HT transporters, have scant in vitro efficacy for the induction of transportermediated 5-HT release and currents. J Neurochem 105: 1770–1780

    Article  PubMed  CAS  Google Scholar 

  • Gobbi M, Mennini T, Garattini S (1997) Mechanism of neurotransmitter release induced by amphetamine derivatives: pharmacological and toxicological aspects. Current Topics in Pharmacology 3: 217–227

    CAS  Google Scholar 

  • Gobbi M, Moia M, Pirona L, Ceglia I, Reyes-Parada M, Scorza C, Mennini T (2002) p-methylthioamphetamine and 1-(m-chlorophenyl)piperazine, two non-neurotoxic 5-HT releasers in vivo, differ from neurotoxic amphetamine derivatives in their mode of action at 5-HT nerve endings in vitro. J Neurochem 82: 1435–1443

    Article  PubMed  CAS  Google Scholar 

  • Gorentla BK, Moritz AE, Foster JD, Vaughan RA (2009) Proline-directed phosphorylation of the dopamine transporter N-terminal domain. Biochemistry 48: 1067–1076

    Article  PubMed  CAS  Google Scholar 

  • Granas C, Ferrer J, Loland CJ, Javitch JA, Gether U (2003) N-terminal truncation of the dopamine transporter abolishes phorbol ester-and substance P receptor-stimulated phosphorylation without impairing transporter internalization. J Biol Chem 278: 4990–5000

    Article  PubMed  CAS  Google Scholar 

  • Guastella J, Nelson N, Nelson H, Czyzyk L, Keynan S, Miedel MC, Davidson N, Lester HA, Kanner BI (1990) Cloning and expression of a rat brain GABA Transporter. Science 249: 1303–1306

    Article  PubMed  CAS  Google Scholar 

  • Hastrup H, Karlin A, Javitch JA (2001) Symmetrical dimer of the human dopamine transporter revealed by cross-linking Cys-306 at the extracellular end of the sixth transmembrane segment. Proc Natl Acad Sci U S A 98: 10 055–10 060

    Article  CAS  Google Scholar 

  • Hilgemann DW, Lu CC (1999) GAT1 (GABA:Na+:Cl-) cotransport function. database reconstruction with an alternating access model. J Gen Physiol 114: 459–475

    Article  PubMed  CAS  Google Scholar 

  • Huang X, Zhan CG (2007) How dopamine transporter interacts with dopamine: insights from molecular modeling and simulation. Biophys J 93: 3627–3639

    Article  PubMed  CAS  Google Scholar 

  • Humphreys CJ, Wall SC, Rudnick G (1994) Ligand binding to the serotonin transporter: equilibria, kinetics, and ion dependence. Biochemistry 33: 9118–9125

    Article  PubMed  CAS  Google Scholar 

  • Indarte M, Madura JD, Surratt CK (2008) Dopamine transporter comparative molecular modeling and binding site prediction using the LeuT(aa) leucine transporter as a template. Proteins 70: 1033–1046

    Article  PubMed  CAS  Google Scholar 

  • Iversen L (2000) Neurotransmitter transporters: fruitful targets for cns drug discovery. Mol Psychiatry 5: 357–362

    Article  PubMed  CAS  Google Scholar 

  • Iversen LL (1971) Role of transmitter uptake mechanisms in synaptic neurotransmission. Br J Pharmacol 41: 571–591

    Article  PubMed  CAS  Google Scholar 

  • Jardetzky O (1966) Simple allosteric model for membrane pumps. Nature 211: 969–970

    Article  PubMed  CAS  Google Scholar 

  • Javitch JA, Blaustein RO, Snyder SH (1984) [3H]Mazindol binding associated with neuronal dopamine and norepinephrine uptake sites. Mol Pharmacol 26: 35–44

    PubMed  CAS  Google Scholar 

  • Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH (1985) Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6 — tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci USA 82: 2173–2177

    Article  PubMed  CAS  Google Scholar 

  • Jess U, Betz H, Schloss P (1996) The membranebound rat serotonin transporter, SERT1, is an oligomeric protein. FEBS Lett 394: 44–46

    Article  PubMed  CAS  Google Scholar 

  • Jones SR, Gainetdinov RR, Wightman RM, Caron MG (1998) Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter. J Neurosci 18: 1979–1986

    PubMed  CAS  Google Scholar 

  • Jones SR, Joseph JD, Barak LS, Caron MG, Wightman RM (1999) Dopamine neuronal transport kinetics and effects of amphetamine. J Neurochem 73: 2406–2414

    Article  PubMed  CAS  Google Scholar 

  • Jorgensen AM, Tagmose L, Jorgensen AM, Topiol S, Sabio M, Gundertofte K, Bogeso KP, Peters GH (2007) Homology modeling of the serotonin transporter: insights into the primary escitalopram-binding site. ChemMedChem 2: 815–826

    Article  PubMed  CAS  Google Scholar 

  • Just H, Sitte HH, Schmid JA, Freissmuth M, Kudlacek O (2004) Identification of an additional interaction domain in transmembrane domains 11 and 12 that supports oligomer formation in the human serotonin transporter. J Biol Chem 279: 6650–6657

    Article  PubMed  CAS  Google Scholar 

  • Kahlig KM, Binda F, Khoshbouei H, Blakely RD, McMahon DG, Javitch JA, Galli A (2005) Amphetamine induces dopamine efflux through a dopamine transporter channel. Proc Natl Acad Sci U S A 102: 3495–3500

    Article  PubMed  CAS  Google Scholar 

  • Kalivas PW, Volkow ND (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162: 1403–1413

    Article  PubMed  Google Scholar 

  • Kantor L, Gnegy ME (1998) Protein kinase c inhibitors block amphetamine-mediated dopamine release in rat striatal slices. J Pharmacol Exp Ther 284: 592–598

    PubMed  CAS  Google Scholar 

  • Kantor L, Hewlett GH, Gnegy ME (1999) Enhanced amphetamine-and k+-mediated dopamine release in rat striatum after repeated amphetamine: differential requirements for Ca2+-and calmodulin-dependent phosphorylation and synaptic vesicles. J Neurosci 19: 3801–3808

    PubMed  CAS  Google Scholar 

  • Kantor L, Hewlett G H, Park YH, Richardson-Burns SM, Mellon MJ, Gnegy ME (2001) Protein kinase C and intracellular calcium are required for amphetamine-mediated dopamine release via the norepinephrine transporter in undifferentiated PC12 cells. J Pharmacol Exp Ther 297: 1016–1024

    PubMed  CAS  Google Scholar 

  • Kazanietz MG, Caloca MJ, Aizman O, Nowicki S (2001) Phosphorylation of the catalytic subunit of rat renal Na+, K+-ATPase by classical PKC isoforms. Arch Biochem Biophys 388: 74–80

    Article  PubMed  CAS  Google Scholar 

  • Khoshbouei H, Sen N, Guptaroy B, Johnson L, Lund D, Gnegy ME, Galli A, Javitch JA (2004) N-terminal phosphorylation of the dopamine transporter is required for amphetamine-induced efflux. PLoS Biol 2:E78

    Article  PubMed  Google Scholar 

  • Khoshbouei H, Wang H, Lechleiter JD, Javitch JA, Galli A (2003) Amphetamine-induced dopamine efflux. a voltage-sensitive and intracellular Na+-dependent mechanism. J Biol Chem 278: 12 070–12 077

    Article  CAS  Google Scholar 

  • Kilic F, Rudnick G (2000) Oligomerization of serotonin tranporter and its functional consequences. Proc Natl Acad Sci U SA 97: 106–3111

    Article  Google Scholar 

  • Kocabas AM, Rudnick G, Kilic F (2003) Functional consequences of homo-but not hetero-oligomerization between transporters for the biogenic amine neurotransmitters. J Neurochem 85: 1513–1520

    Article  PubMed  CAS  Google Scholar 

  • Korkhov VM, Holy M, Freissmuth M, Sitte HH (2006) The conserved glutamate (Glu136) in transmem-brane domain 2 of the serotonin transporter is required for the conformational switch in the transport cycle. J Biol Chem 281: 13439–13448

    Article  PubMed  CAS  Google Scholar 

  • Kuhar MJ, Ritz MC, Boja JW (1991) The dopamine hypothesis of the reinforcing properties of cocaine. Trends Neurosci 14: 299–302

    Article  PubMed  CAS  Google Scholar 

  • L’hirondel M, Cheramy A, Godeheu G, Glowinski J (1995) Effects of arachidonic acid on dopamine synthesis, spontaneous release, and uptake in striatal synaptosomes from the rat. J Neurochem 64: 1406–1409

    Article  CAS  Google Scholar 

  • Langston JW, Irwin I, Langston EB, Forno LS (1984) 1-methyl-4-phenylpyridinium ion (MPP+): identification of a metabolite of MPTP, a toxin selective to the substantia nigra. Neurosci Lett 48: 87–92

    Article  PubMed  CAS  Google Scholar 

  • Loland CJ, Desai RI, Zou MF, Cao J, Grundt P, Gerstbrein K, Sitte HH, Newman AH, Katz JL, Gether U (2008) Relationship between conformational changes in the dopamine transporter and cocaine-like subjective effects of uptake inhibitors. Mol Pharmacol 73: 813–823

    Article  PubMed  CAS  Google Scholar 

  • Lu CC, Hilgemann DW (1999a) GAT1 (GABA:Na+:Cl-) cotransport function. kinetic studies in giant xenopus oocyte membrane patches. J Gen Physiol 114: 445–457

    Article  PubMed  CAS  Google Scholar 

  • Lu CC, Hilgemann DW (1999 b) GAT1 (GABA:Na+:Cl-) cotransport function. steady state studies in giant xenopus oocyte membrane patches. J Gen Physiol 114: 429–444

    Article  PubMed  CAS  Google Scholar 

  • Martell BA, Orson FM, Poling J, Mitchell E, Rossen RD, Gardner T, Kosten TR (2009) Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients: a randomized, double-blind, placebo-controlled efficacy trial. Arch Gen Psychiatry 66: 1116–1123

    Article  PubMed  CAS  Google Scholar 

  • Masson J, Sagne C, Hamon M, el Mestikawy S (1999) Neurotransmitter transporters in the central nervous system. Pharmacol Rev 51: 439–464

    PubMed  CAS  Google Scholar 

  • Mazei-Robinson MS, Blakely RD (2006) ADHD and the dopamine transporter: are there reasons to pay attention? Handb Exp Pharmacol 373–415

    Google Scholar 

  • Mazei-Robison MS, Bowton E, Holy M, Schmudermaier M, Freissmuth M, Sitte HH, Galli A, Blakely RD (2008) Anomalous dopamine release associated with a human dopamine transporter coding variant. J Neurosci 28: 7040–7046

    Article  PubMed  CAS  Google Scholar 

  • Meinild AK, Sitte HH, Gether U (2004) Zinc Potentiates an Uncoupled Anion Conductance Associated With the Dopamine Transporter. J Biol Chem 279: 49 671–49 679.

    Article  CAS  Google Scholar 

  • Moron JA, Zakharova I, Ferrer J V, Merrill GA, Hope B, Lafer EM, Lin ZC, Wang J B, Javitch JA, Galli A, Shippenberg TS (2003) Mitogen-activated protein kinase regulates dopamine transporter surface expression and dopamine transport apacity. J Neurosci 23: 8480–8488

    PubMed  CAS  Google Scholar 

  • Nelson N (1998) The family of Na+/Cl-neurotransmitter transporters. J Neurochem 71: 1785–1803

    Article  PubMed  CAS  Google Scholar 

  • Nestler EJ (2005) Is there a common molecular pathway for addiction? Nat Neurosci 8: 1445–1449

    Article  PubMed  CAS  Google Scholar 

  • Nirenberg MJ, Chan J, Vaughan RA, Uhl GR, Kuhar MJ, Pickel VM (1997) Immunogold localization of the dopamine transporter: an ultrastructural study of the rat ventral tegmental area. J Neurosci 17: 5255–5262

    PubMed  CAS  Google Scholar 

  • Pacholczyk T, Blakely RD, Amara SG (1991) Expression cloning of a cocaine-and antidepressantsensitive human noradrenaline transporter. Nature 350: 350–354

    Article  PubMed  CAS  Google Scholar 

  • Pifl C, Agneter E, Drobny H, Reither H, Singer EA (1997) Induction by low Na+ or Cl-of cocaine sensitive carrier-mediated efflux of amines from cells transfected with the cloned human catecholamine transporters. Br J Pharmacol 121: 205–212

    Article  PubMed  CAS  Google Scholar 

  • Pifl C, Agneter E, Drobny H, Sitte HH, Singer EA (1999) Amphetamine reverses or blocks the operation of the human noradrenaline transporter depending on its concentration: superfusion studies on transfected cells. Neuropharmacology 38: 157–165

    Article  PubMed  CAS  Google Scholar 

  • Pifl C, Drobny H, Reither H, Hornykiewicz O, Singer EA (1995) Mechanism of the dopamine-releasing actions of amphetamine and cocaine: plasmalemmal dopamine transporter versus vesicular monoamine transporter. Mol Pharmacol 47: 368–373

    PubMed  CAS  Google Scholar 

  • Pifl C, Singer EA (1999) Ion dependence of carriermediated release in dopamine or norepinephrine transporter-transfected cells questions the hypothesis of facilitated exchange diffusion. Mol Pharmacol 56: 1047–1054

    PubMed  CAS  Google Scholar 

  • Pozzan T, Gatti G, Dozio N, Vicentini LM, Meldolesi J (1984) Ca2+-dependent and-independent release of neurotransmitters from PC12 cells: a role for protein kinase C activation? J Cell Biol 99: 628–638

    Article  PubMed  CAS  Google Scholar 

  • Ramamoorthy S, Blakely RD (1999) Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants. Science 285: 763–766

    Article  PubMed  CAS  Google Scholar 

  • Ramamoorthy S, Samuvel DJ, Buck ER, Rudnick G, Jayanthi LD (2007) Phosphorylation of threonine residue 276 is required for acute regulation of serotonin transporter by cyclic GMP. J Biol Chem 282: 11 639–11 647

    CAS  Google Scholar 

  • Robertson SD, Matthies HJ, Galli A (2009) A closer look at amphetamine-induced reverse transport and trafficking of the dopamine and norepinephrine transporters. Mol Neurobiol 39: 73–80

    Article  PubMed  CAS  Google Scholar 

  • Ross SB, Renyi AL (1966) Uptake of some tritiated sympathomimetic amines by mouse brain cortex slices in vitro. Acta Pharmacol Toxicol (Copenh) 24: 297–309

    Article  CAS  Google Scholar 

  • Roux MJ, Supplisson S (2000) Neuronal and glial glycine transporters have different stoichiometries. Neuron 25: 373–383

    Article  PubMed  CAS  Google Scholar 

  • Rudnick G (2006) Structure/function relationship in serotonin transporter. In: Sitte HH, Freissmuth M (eds) Neurotransmitter transporters pp 59–73, Springer-Verlag, Berlin Heidelberg

    Chapter  Google Scholar 

  • Rudnick G, Clark J (1993) From synapse to vesicle: the reuptake and storage of biogenic amine neurotransmitters. Biochim Biophys Acta 1144: 249–263

    Article  PubMed  CAS  Google Scholar 

  • Rudnick G, Wall SC (1992) p-chloroamphetamine induces serotonin release through serotonin transporters. Biochemistry 31: 6710–6718

    Article  PubMed  CAS  Google Scholar 

  • Saier MH Jr., Tran CV, Barabote RD (2006) TCDB: the transporter classification database for membrane transport protein analyses and information. Nucleic Acids Res 34:D181–D186

    Article  PubMed  CAS  Google Scholar 

  • Saunders C, Ferrer JV, Shi L, Chen J, Merrill G, Lamb ME, Leeb-Lundberg LM, Carvelli L, Javitch JA, Galli A (2000) Amphetamine-induced loss of human dopamine transporter activity: an internalization-dependent and cocaine-sensitive mechanism. Proc Natl Acad Sci USA 97: 6850–6855

    Article  PubMed  CAS  Google Scholar 

  • Schmid JA, Scholze P, Kudlacek O, Freissmuth M, Singer EA, Sitte HH (2001) Oligomerization of the human serotonin transporter and of the rat GABA transporter 1 visualized by fluorescence resonance energy transfer microscopy in living cells. J Biol Chem 276: 3805–3810

    Article  PubMed  CAS  Google Scholar 

  • Scholze P, Freissmuth M, Sitte HH (2002 a) Mutations within an intramembrane leucine heptad repeat disrupt oligomer formation of the rat GABA transporter 1. J Biol Chem 277: 43 682–43 690

    CAS  Google Scholar 

  • Scholze P, Norregaard L, Singer EA, Freissmuth M, Gether U, Sitte HH (2002 b) The role of zinc ions in reverse transport mediated by monoamine Transporters. J Biol Chem 277: 21 505–21 513

    CAS  Google Scholar 

  • Scholze P, Zwach J, Kattinger A, Pifl C, Singer EA, Sitte HH (2000) Transporter-Mediated Release: A superfusion study on human embryonic kidney cells stably expressing the human serotonin transporter. J Pharmacol Exp Ther 293: 870–878

    PubMed  CAS  Google Scholar 

  • Seidel S, Singer EA, Just H, Farhan H, Scholze P, Kudlacek O, Holy M, Koppatz K, Krivanek P, Freissmuth M, Sitte HH (2005) Amphetamines take two to tango: an oligomer-based counter-transport model of neurotransmitter transport explores the amphetamine action. Mol Pharmacol 67: 140–151

    PubMed  CAS  Google Scholar 

  • Seiden LS, Sabol KE, Ricaurte GA (1993) Amphetamine: effects on catecholamine systems and behavior. Annu Rev Pharmacol Toxicol 33: 639–677

    Article  PubMed  CAS  Google Scholar 

  • Sen N, Shi L, Beuming T, Weinstein H, Javitch JA (2005) A pincer-like configuration of TM2 in the human dopamine transporter is responsible for indirect effects on cocaine binding. Neuropharmacology 49: 780–790

    Article  PubMed  CAS  Google Scholar 

  • Shi L, Quick M, Zhao Y, Weinstein H, Javitch JA (2008) The mechanism of a neurotransmitter: sodium symporter-inward release of Na+ and substrate is triggered by substrate in a second binding site. Mol Cell 30: 667–677

    Article  PubMed  CAS  Google Scholar 

  • Singh SK (2008) LeuT: a prokaryotic stepping stone on the way to a eukaryotic neurotransmitter transporter structure. Channels (Austin) 2: 380–389

    Article  Google Scholar 

  • Singh SK, Piscitelli CL, Yamashita A, Gouaux E (2008) A competitive inhibitor traps leut in an open-toout conformation. Science 322: 1655–1661

    Article  PubMed  CAS  Google Scholar 

  • Sitte HH, Farhan H, Javitch JA (2004) Sodium-dependent neurotransmitter transporters: oligomerization as a determinant of transporter function and trafficking. Mol Interv 4: 38–47

    Article  PubMed  CAS  Google Scholar 

  • Sitte HH, Freissmuth M (2003) Oligomer formation by Na+-Cl-coupled neurotransmitter transporters. Eur J Pharmacol 479: 229–236

    Article  PubMed  CAS  Google Scholar 

  • Sitte HH, Hiptmair B, Zwach J, Pifl C, Singer EA, Scholze P (2001) Quantitative analysis of inward and outward transport rates in cells stably expressing the cloned human serotonin transporter: inconsistencies with the hypothesis of facilitated exchange diffusion. Mol Pharmacol 59: 1129–1137

    PubMed  CAS  Google Scholar 

  • Sitte HH, Huck S, Reither H, Boehm S, Singer EA, Pifl C (1998) Carrier-mediated release, transport rates, and charge transfer induced by amphetamine, tyramine, and dopamine in mammalian cells transfected with the human dopamine transporter. J Neurochem 71: 1289–1297

    Article  PubMed  CAS  Google Scholar 

  • Sitte HH, Scholze P, Schloss P, Pifl C, Singer EA (2000) Characterization of carrier-mediated release in human embryonic kidney 293 cells stably expressing the rat serotonin transporter: a superfusion study. J Neurochem 74: 1317–1324

    Article  PubMed  CAS  Google Scholar 

  • Sitte HH, Singer EA, Scholze P (2002) Bi-directional transport of gaba in human embryonic kidney (HEK-293) cells stably expressing the rat GABA Transporter GAT-1. Br J Pharmacol 135: 93–102

    Article  PubMed  CAS  Google Scholar 

  • Sorkina T, Doolen S, Galperin E, Zahniser NR, Sorkin A (2003) Oligomerization of dopamine transporters visualized in living cells by FRET microscopy. J Biol Chem 278: 28 274–28 283

    Article  CAS  Google Scholar 

  • Sulzer D, Sonders M S, Poulsen NW, Galli A (2005) Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol 75: 406–433

    Article  PubMed  CAS  Google Scholar 

  • Torres GE, Carneiro A, Seamans K, Fiorentini C, Sweeney A, Yao WD, Caron MG (2003 a) Oligomerization and trafficking of the human dopamine transporter. mutational analysis identifies critical domains important for the functional expression of the transporter. J Biol Chem 278: 2731–2739

    Article  PubMed  CAS  Google Scholar 

  • Torres GE, Gainetdinov RR, Caron MG (2003 b) Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 4: 13–25

    Article  PubMed  CAS  Google Scholar 

  • Trendelenburg U, Langeloh A, Bönisch H (1987) Mechanism of action of indirectly acting sympathomimetic amines. Blood Vessels 24: 261–270

    PubMed  CAS  Google Scholar 

  • Wall SC, Gu H, Rudnick G (1995) Biogenic amine flux mediated by cloned transporters stably expressed in cultured cell lines: amphetamine specificity for inhibition and efflux. Mol Pharmacol 47: 544–550

    PubMed  CAS  Google Scholar 

  • Wang D, Deken SL, Whitworth TL, Quick MW (2003) Syntaxin 1A inhibits GABA flux, efflux, and exchange mediated by the rat brain GABA transporter GAT1. Mol Pharmacol 64: 905–913

    Article  PubMed  CAS  Google Scholar 

  • Wolfel R, Graefe KH (1992) Evidence for various tryptamines and related compounds acting as substrates of the platelet 5-hydroxytryptamine transporter. Naunyn Schmiedebergs Arch Pharmacol 345: 129–136

    Article  PubMed  CAS  Google Scholar 

  • Yamashita A, Singh SK, Kawate T, Jin Y, Gouaux E (2005) Crystal structure of a bacterial homologue of Na+/Cl-dependent neurotransmitter transporters. Nature 437: 215–223

    Article  PubMed  CAS  Google Scholar 

  • Zaczek R, Culp S, De SE (1991) Interactions of [3H] amphetamine with rat brain synaptosomes. II. active transport. J Pharmacol Exp Ther 257: 830–835

    PubMed  CAS  Google Scholar 

  • Zhu CB, Carneiro AM, Dostmann WR, Hewlett WA, Blakely RD (2005) P38 MAPK activation elevates serotonin transport activity via a trafficking-independent, protein phosphatase 2A-dependent process. J Biol Chem 280: 15649–15658

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Life Sciences Department of Medical / Pharmaceutical Chemistry, University of Vienna, Althanstr.14, 1090, Vienna, Austria

    René Weissensteiner, Andreas Jurik & Gerhard F. Ecker

  2. Center of Biomolecular Medicine and Pharmacology Institute of Pharmacology, Medical University of Vienna, Waehringerstr.13a, 1090, Vienna, Austria

    Thomas Steinkellner, Simon Bulling, Walter Sandtner, Oliver Kudlacek, Michael Freissmuth & Harald H. Sitte

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  1. René Weissensteiner
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  2. Thomas Steinkellner
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  3. Andreas Jurik
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  1. Department of Neurobiology, Faculty of Life Sciences, University of Vienna, Vienna, Austria

    Friedrich G. Barth

  2. Institute of Philosophy, University of Vienna, Austria

    Patrizia Giampieri-Deutsch  & Hans-Dieter Klein  & 

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Weissensteiner, R. et al. (2012). Towards an understanding of the psychostimulant action of amphetamine and cocaine. In: Barth, F.G., Giampieri-Deutsch, P., Klein, HD. (eds) Sensory Perception. Springer, Vienna. https://doi.org/10.1007/978-3-211-99751-2_11

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