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Schmitt & Reith DAT Regulation methamphetamine users typically take upward of 100 mg (a “point”) per dose session—for those that administer it via inhalation (as smoked “crystal meth” or “ice”), this can be even higher—often taking multiple subsequent doses in a “binge” pattern (every few hours); chronic methamphetamine addicts can easily consume doses on the order of grams per day. 145 Intranasal administration of a 50mg dose of d-methamphetamine results in an average plasma concentration of 758 nM in human subjects. 148 Sequential 100-mg doses could thus result in prolonged plasma drug concentrations ranging into the micromolar levels shown in animal and in vitro studies to elicit profound dopamine release, cytotoxicity, and long-lasting downregulation of DAT function. Methamphetamine addicts that consume gram quantities per day can achieve steady-state plasma concentrations exceeding 13 �M. 74 Hence, it is likely that the transient reduction in plasmalemmal DAT expression observed after a single high-level dose of methamphetamine and the prolonged reduction seen in chronic high-dose methamphetamine users are two entirely different phenomena: the former representing a neuroadaptive feedback mechanism and the latter representing accumulated apoptotic oxidative injury to dopaminergic neurons. Conclusion Neuronal DATs are the primary regulators of extracellular dopamine in the brain and are thus responsible for both the duration and the magnitude of interneuronal dopaminergic signals. Biogenic amine transporter proteins, such as the DAT, are highly dynamic entities that rapidly cycle between the plasma membrane and early endosomal compartments, probably in specialized vesicles roughly similar to synaptic vesicles in size (e.g., Ref. 19). By altering the pattern of DAT trafficking, cells can adjust the number of active (surface localized) DATs in real time, allowing for condition-specific adaptive changes in dopaminergic signaling. DAT trafficking is regulated by several intracellular signaling cascades involving protein kinases and phosphatases. Activation or inhibition of PKC, PI3K, and members of the MAPK family can trigger transporter membrane redistribution; however, the identity of the kinase(s) ultimately responsible for direct phosphorylation of the DAT is currently unknown. With the recent evidence that syntaxin 1A and other scaffolding proteins interact with the DAT, it is certainly conceivable that central signaling kinases, such as PKC, affect DAT activity via DAT-associated scaffolding or cytoskeletal proteins that more directly control the transporter’s trafficking fate. In addition, ligands for certain presynaptic GPCRs found on dopaminergic neurons (such as dopamine D2like autoreceptors and �-opioid receptors) can also acutely regulate DAT surface presence, probably by modulating the activity of these cell signal transduction pathways. Finally, DAT trafficking is acutely regulated by ligands that directly interact with the DAT itself (substrates and inhibitors). Acute exposure to high doses of substrates (including several amphetaminergic compounds and dopamine itself) elicits a biphasic effect on DAT trafficking: initially, a rapid yet transient (beginning within seconds and lasting for several minutes) increase in surface DAT occurs, followed by significant transporter endocytosis that begins after approximately 15 min of substrate exposure. In direct contrast with the internalizing effects of substrates, cocaine-like DAT inhibitors appear to induce upregulation of surface DAT levels. Upregulation of surface DAT concentration might be responsible for much of the anhedonic, depressionlike symptoms that chronic cocaine addicts experience during withdrawal—doubtless triggering cravings for more cocaine. The DAT-internalizing effect of substrates, such as d-amphetamine, might thus be useful in ameliorating symptoms of cocaine withdrawal. In limited preclinical trials, d-amphetamine has shown efficacy in reducing cocaine consumption and craving. 43 Amphetaminergic prodrugs would be desirable for this purpose, because their requisite metabolic activation after oral administration and slow onset of action would prevent the possibility of parenteral abuse, a clear concern in psychostimulant-addicted patients. The atypical psychostimulant compound modafinil also shows preclinical promise as a potential therapeutic for stimulant addiction. Modafinil decreases cocaine craving during withdrawal 149 and attenuates the effect of concomitantly administered cocaine 150 or methamphetamine, 151 warranting investigation into its effects on DAT trafficking. There is also evidence that withdrawal from psychostimulant use is associated with deficits in not only dopaminergic but also serotonergic function. Moreover, agents Ann. N.Y. Acad. Sci. 1187 (2010) 316–340 c○ 2010 New York Academy of Sciences. 333
DAT Regulation Schmitt & Reith that increase serotonergic activity can attenuate reinforcing effects mediated by excessive dopamine release. 152 Therefore, novel amphetaminergic substrates functioning as dual dopamine/serotonin releasers—but lacking the prooxidant metabolites of MDA-like compounds or the 5-HT2B receptor agonist activity of fenfluramine and its metabolites— may be beneficial as treatment agents. 153 Conflicts of interest The authors declare no conflicts of interest. References 1. Gether, U., P.H. Andersen, O.M. Larsson & A. Schousboe. 2006. Neurotransmitter transporters: molecular function of important drug targets. Trends Pharmacol. Sci. 27: 375–383. 2. Volz, T.J. & J.O. Schenk. 2005. A comprehensive atlas of the topography of functional groups of the dopamine transporter. Synapse 58: 72–94. 3. Gainetdinov, R.R. & M.G. Caron. 2003. Monoamine transporters: from genes to behavior. Annu. Rev. Pharmacol. Toxicol. 43: 261–284. 4. Mortensen, O. & S. Amara. 2003. Dynamic regulation of the dopamine transporter. Eur. J. Pharmacol. 479: 159–170. 5. Mash, D.C. 2008. Dopamine transporter, disease states and pathology. In Dopamine Transporters: Chemistry, Biology and Pharmacology. M.L.Trudell&S.Izenwasser, Eds.: 29–47. Wiley. Hoboken, NJ. 6. Giros,B.,M.Jaber,S.R.Jones,et al. 1996. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379: 606–612. 7. Rocha, B.A., F. Fumagalli, R.R. Gainetdinov, et al. 1998. Cocaine self-administration in dopamine-transporter knockout mice. Nat. Neurosci. 1: 132–137. 8. Mateo, Y., E.A. Budygin, C.E. John & S.R. Jones. 2004. Role of serotonin in cocaine effects in mice with reduced dopamine transporter function. Proc. Natl. Acad. Sci. USA 101: 372–377. 9. Chen, R., M.R. Tilley, H. Wei, et al. 2006. Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter. Proc. Natl. Acad. Sci. USA 103: 9333–9338. 10. Tilley, M.R., B. Cagniard, X. Zhuang, et al. 2007. Cocaine reward and locomotion stimulation in mice with reduced dopamine transporter expression. BMC Neurosci. 8: 42. (online). 11. Thomsen, M., F.S. Hall, G.R. Uhl & S.B. Caine. 2009. Dramatically decreased cocaine self-administration in dopamine but not serotonin transporter knock-out mice. J. Neurosci. 29: 1087–1092. 12. Jones, S.R., R.R. Gainetdinov, M. Jaber, et al. 1998. Profound neuronal plasticity in response to inactivation of the dopamine transporter. Proc. Natl. Acad. Sci. USA 95: 4029–4034. 13. Rice, M.E. & S.J. Cragg. 2008. Dopamine spillover after quantal release: rethinking dopamine transmission in the nigrostriatal pathway. Brain Res. Rev. 58: 303– 313. 14. Kimmel, H.L., F.I. Carroll & M.J. Kuhar. 2000. Dopamine transporter synthesis and degradation rate in rat striatum and nucleus accumbens using RTI-76. Neuropharmacology 39: 578–585. 15. Kimmel, H.L., F.I. Carroll & M.J. Kuhar. 2003. Withdrawal from repeated cocaine alters dopamine transporterproteinturnoverintheratstriatum.J.Pharmacol. Exp. Ther. 304: 15–21. 16. Gulley, J.M. & N.R. Zahniser. 2003. Rapid regulation of dopamine transporter function by substrates, blockers and presynaptic receptor ligands. Eur. J. Pharmacol. 479: 139–152. 17. Zahniser, N.R. & A. Sorkin. 2004. Rapid regulation of the dopamine transporter: role in stimulant addiction? Neuropharmacology 47: 80–91. 18. Hille, B. 2001. Ion Channels of Excitable Membranes,3rd edn. Sinauer Associates Publishing. Sunderland, MA. 19. Deken, S.L., D. Wang & M. Quick. 2003. Plasma membrane GABA transporters reside on distinct vesicles and undergo rapid regulated recycling. J. Neurosci. 23: 1563–1568. 20. Goodwin, J.S., G.A. Larson, J. Swant, et al. 2009. Amphetamine and methamphetamine differentially affect dopamine transporters in vitro and in vivo. J. Biol. Chem. 284: 2978–2989. 21. Fleckenstein, A.E., R.R. Metzger, D.G. Wilkins, et al. 1997. Rapid and reversible effects of methamphetamine on dopamine transporters. J. Pharmacol. Exp. Ther. 282: 834–838. 22. Kokoshka, J.M., R.A. Vaughan, G.R. Hanson & A.E. Fleckenstein. 1998. Nature of methamphetamineinduced rapid and reversible changes in dopamine transporters. Eur. J. Pharmacol. 361: 269–275. 23. Saunders, C., J.V. Ferrer, L. Shi, et al. 2000. Amphetamine-induced loss of human dopamine transporter activity: an internalization-dependent and cocaine-sensitive mechanism. Proc.Natl.Acad.Sci.USA 97: 6850–6855. 334 Ann. N.Y. Acad. Sci. 1187 (2010) 316–340 c○ 2010 New York Academy of Sciences.
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