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. 2005 Dec 20;7(4):E847–E851. doi: 10.1208/aapsj070481

Role of monoamine transporters in mediating psychostimulant effects

Evan L Riddle 1, Annette E Fleckenstein 1, Glen R Hanson 1,✉
PMCID: PMC2750953  PMID: 16594636

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

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References

  • 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. doi: 10.1016/0304-3940(91)90869-U. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0166-4328(97)00177-0. [DOI] [PubMed] [Google Scholar]
  • 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. [PubMed] [Google Scholar]
  • 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. doi: 10.1046/j.1471-4159.2000.0742217.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1124/jpet.104.072264. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1124/jpet.302.2.497. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0014-2999(02)01985-4. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1523/JNEUROSCI.22-19-08705.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1046/j.1471-4159.1999.0721266.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1126/science.2820058. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/0376-8716(91)90086-E. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0014-2999(99)00588-9. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1006/bbrc.2002.6384. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1046/j.1471-4159.2002.00820.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1124/jpet.102.045005. [DOI] [PubMed] [Google Scholar]
  • 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. [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0014-2999(03)02080-6. [DOI] [PubMed] [Google Scholar]
  • 18.Truong JG, Hanson GR, Fleckenstein AE. Apomorphine increases vesicular monoamine transporter-2 function: implications for neurodegeneration. Eur J Pharmacol. 2004;492:143–147. doi: 10.1016/j.ejphar.2004.03.060. [DOI] [PubMed] [Google Scholar]
  • 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. 2004;504:27–32. doi: 10.1016/j.ejphar.2004.09.049. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/0896-6273(90)90339-H. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1523/JNEUROSCI.15-05-04102.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Liang NY, Rutledge CO. Evidence for carrier-mediated efflux of dopamine from corpus striatum. Biochem Pharmacol. 1982;31:2479–2484. doi: 10.1016/0006-2952(82)90057-0. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1073/pnas.0407737102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0014-2999(97)00148-9. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1073/pnas.110035297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0014-2999(00)00639-7. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1523/JNEUROSCI.0387-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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.
  • 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. doi: 10.1523/JNEUROSCI.14-04-02260.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/0006-8993(90)90467-P. [DOI] [PubMed] [Google Scholar]

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