The AAPS Journal

, Volume 7, Issue 4, pp E847–E851 | Cite as

Role of monoamine transporters in mediating psychostimulant effects

  • Evan L. Riddle
  • Annette E. Fleckenstein
  • Glen R. Hanson
Article

Abstract

Monoamine transporters such as the dopamine (DA) transporter (DAT) and the vesicular monoamine transporter-2 (VMAT-2) are critical regulators of DA disposition within the brain. Alterations in DA disposition can lead to conditions such as drug addiction, Parkinson’s disease, and schizophrenia, a fact that underscores the importance of understanding DAergic signaling. Psychostimulants alter DAergic signaling by influencing both DAT and VMAT-2, and although the effects of these drugs result in increased levels of synaptic DA, the mechanisms by which this occurs and the effects that these drugs exert on DAT and VMAT-2 vary. Many psychostimulants can be classified as releasers (ie, amphetamine analogs) or uptake blockers (ie, cocaine-like drugs) based on the mechanism of their acute effects on neurotransmitter flux through the DAT. Releasers and uptake blockers differentially modulate the activity and subcellular distribution of monoamine transporters, a phenomenon likely related to the neurotoxics potential of these drugs to DAergic neurons. This article will review some of the recent findings whereby releasers and uptake blockers alter DAT and VMAT-2 activity and how these alterations may be involved in neurotoxicity, thus providing insight on the neuro-degeneration observed in Parkinson’s disease.

Keywords

dopamine transporter vesicular monoamine transporter-2 amphetamine cocaine methylphenidate Parkinson’s disease 

References

  1. 1.
    Butcher SP, Liptrot J, Aburthnott GW. Characterisation of methylphenidate and nomifensine induced dopamine release in rat striatum using in vivo microdialysis.Neurosci Lett. 1991;122:245–248.PubMedCrossRefGoogle Scholar
  2. 2.
    Russell V, de Viliers A, Sagvolden T, Lamm M, Taljaard J. Differences between electrically-, Ritalin-, and D-amphetamine-stimulated release of [3H]dopamine from brain slices suggest impaired storage of dopamine in an animal model of attention-deficit hyperactivity disorder.Behav Brain Res. 1998;94:163–171.PubMedCrossRefGoogle Scholar
  3. 3.
    Horn AS, Coyle JT, Snyder SH. Catecholamine uptake by synaptosomes from rat brain: structure-activity relationships of drugs with differential effects on dopamine and norepinephrine neurons.Mol Pharmacol. 1971;7:66–80.PubMedGoogle Scholar
  4. 4.
    Hogan KA, Staal RG, Sonsalla PK. Analysis of VMAT2 binding after methamphetamine or MPTP treatment: disparity between homogenates and vesicle preparations.J Neurochem. 2000;74:2217–2220.PubMedCrossRefGoogle Scholar
  5. 5.
    Eyerman DJ, Yamamoto BK. Lobeline attenuates methamphetamine-induced changes in vesicular monoamine transporter 2 immunoreactivity and monoamine depletions in the striatum.J Pharmacol Exp Ther. 2005;312:160–169.PubMedCrossRefGoogle Scholar
  6. 6.
    Brown JM, Riddle EL, Sandoval V, et al. A single methamphetamine administration rapidly decreases vesicular dopamine uptake.J Pharmacol Exp Ther. 2002;302:497–501.PubMedCrossRefGoogle Scholar
  7. 7.
    Riddle EL, Topham MK, Haycock JW, Hanson GR, Fleckenstein AE. Differential trafficking of the vesicular monoamine transporter-2 by methamphetamine and cocaine.Eur J Pharmacol. 2002;449:71–74.PubMedCrossRefGoogle Scholar
  8. 8.
    Sandoval V, Riddle EL, Hanson GR, Fleckenstein AE. Methylphenidate redistributes vesicular monoamine transporter-2: role of dopamine receptors.J Neurosci. 2002;22:8705–8710.PubMedGoogle Scholar
  9. 9.
    Wayment HK, Deutsch H, Schweri MM, Schenk JO. Effects of methylphenidate analogues on phenethylamine substrates for the striatal dopamine transporter: potential as amphetamine antagonists.J Neurochem. 1999;72:1266–1274.PubMedCrossRefGoogle Scholar
  10. 10.
    Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ. Cocaine receptors on dopamine transporters are related to self-administration of cocaine.Science. 1987;237:1219–1223.PubMedCrossRefGoogle Scholar
  11. 11.
    Yeh SY, De Souza EB. Lack of neurochemical evidence for neurotoxic effects of repeated cocaine administration in rats on brain monoamine neurons.Drug Alcohol Depend. 1991;27:51–61.PubMedCrossRefGoogle Scholar
  12. 12.
    Fleckenstein AE, Haughey HM, Metzger RR, et al. Differential effects of psychostimulants and related agents on dopaminergic and serotonergic transporter function.Eur J Pharmacol. 1999;382:45–49.PubMedCrossRefGoogle Scholar
  13. 13.
    Daws LC, Callaghan PD, Moron JA, et al. Cocaine increases dopamine uptake and cell surface expression of dopamine transporters.Biochem Biophys Res Commun. 2002;290:1545–1550.PubMedCrossRefGoogle Scholar
  14. 14.
    Mash DC, Pablo J, Ouyang Q, Hearn WL, Izenwasser S. Dopamine transport function is elevated in cocaine users.J Neurochem. 2002;81:292–300.PubMedCrossRefGoogle Scholar
  15. 15.
    Sandoval V, Riddle EL, Hanson GR, Fleckenstein AE. Methylphenidate alters vesicular monoamine transport and prevents methamphetamine-induced dopaminergic deficits.J Pharmacol Exp Ther. 2003;304:1181–1187.PubMedCrossRefGoogle Scholar
  16. 16.
    Brown JM, Hanson GR, Fleckenstein AE. Cocaine-induced increases in vesicular dopamine uptake: role of dopamine receptors.J Pharmacol Exp Ther. 2001;298:1150–1153.PubMedGoogle Scholar
  17. 17.
    Truong JG, Rau KS, Hanson GR. Fleckenstein. Pramipexole increases vesicular dopamine uptake: implications for treatment of Parkinson’s neurodegeneration.Eur J Pharmacol. 2003;474: 223–226.PubMedCrossRefGoogle Scholar
  18. 18.
    Truong JG, Hanson GR, Fleckenstein AE. Apomorphine increases vesicular monoamine transporter-2 function: implications for neurodegeneration.Eur J Pharmacol. 2004a,492:143–147.PubMedCrossRefGoogle Scholar
  19. 19.
    Truong JG, Newman AH, Hanson GR, Fleckenstein AE. Dopamine D2 receptor activation increases vesicular dopamine uptake and redistributes vesicular monoamine transporter-2 protein.Eur J Pharmacol. 2004b;504:27–32.PubMedCrossRefGoogle Scholar
  20. 20.
    Sulzer D, Rayport S. Am phetamine and other psychostimulants reduce pH gradients in midbrain dopamine neurons and chromaffin granules: a mechanism of action.Neuron. 1990;5:797–808.PubMedCrossRefGoogle Scholar
  21. 21.
    Sulzer D, Chen TK, Lau YY, Kristensen H, Rayport S, Ewing A. Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport.J Neurosci. 1995;15:4102–4108.PubMedGoogle Scholar
  22. 22.
    Liang NY, Rutledge CO. Evidence for carrier-mediated efflux of dopamine from corpus striatum.Biochem Pharmacol. 1982;31:2479–2484.PubMedCrossRefGoogle Scholar
  23. 23.
    Kahlig KM, Binda F, Khoshbouei H, et al. Amphetamine induces dopamine efflux through a dopamine transporter channel.Proc Natl Acad Sci USA 2005;102:3495–3500.PubMedCrossRefGoogle Scholar
  24. 24.
    Fleckenstein AE, Metzger RR, Gibb JW, Hanson GR. A rapid and reversible change in dopamine transporters induced by metham phetamine.Eur J Pharmacol. 1997;323:R9–10.PubMedCrossRefGoogle Scholar
  25. 25.
    Saunders C, Ferrer JV, Shi L, et al. Amphetamine-induced loss of human dopamine transporter activity: an internalization-dependent and cocaine sensitive mechanism.Proc Natl Acad Sci USA. 2000;97:6850–6855.PubMedCrossRefGoogle Scholar
  26. 26.
    Fleckenstein AE, Gibb JW, Hanson GR. Differential effects of stimulants on monoaminergic transporters: pharmacological consequences and implications for neurotoxicity.Eur J Pharmacol. 2000;406:1–13.PubMedCrossRefGoogle Scholar
  27. 27.
    Baucum AJ, Rau KS, Riddle EL, Hansons GR, Fleckenstein AE. Methamphetamine increases dopamine transporter higher molecular weight complex formation via a dopamine-and hyperthermia-associated mechanisms.J Neurosci. 2004;24:3436–3443.PubMedCrossRefGoogle Scholar
  28. 28.
    Baucum AJ, Cook GA, Hanson JE, Hanson GR, Fleckenstein AE. Reactive oxygen species contribute to dopamine transporter oligomerization [abstract].Exp Biol. 2005; Abstract 312.6.Google Scholar
  29. 29.
    Cubells JF, Rayport S, Rajendran G, Sulzer D. Methamphetamine neurotoxicity involves vacuolation of endocytic organelles and dopamine-dependent intracellular oxidative stress.J Neurosci. 1994;14:2260–2271.PubMedGoogle Scholar
  30. 30.
    Marek GJ, Vosmer G, Seiden LS. Dopamine uptake inhibitors block long-term neurotoxic effects of methamphetamine upon dopaminergic neurons.Brain Res. 1990;517:274–279.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2005

Authors and Affiliations

  • Evan L. Riddle
    • 1
  • Annette E. Fleckenstein
    • 1
  • Glen R. Hanson
    • 1
  1. 1.Department of Pharmacology and ToxicologyUniversity of UtahSalt Lake City

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