Skip to main content
SpringerLink
Log in

Molecular Mechanisms of Amphetamines

  • Chapter
  • First Online:
Substance Use Disorders

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 258))

Abstract

There is a plethora of amphetamine derivatives exerting stimulant, euphoric, anti-fatigue, and hallucinogenic effects; all structural properties allowing these effects are contained within the amphetamine structure. In the first part of this review, the interaction of amphetamine with the dopamine transporter (DAT), crucially involved in its behavioral effects, is covered, as well as the role of dopamine synthesis, the vesicular monoamine transporter VMAT2, and organic cation 3 transporter (OCT3). The second part deals with requirements in amphetamine’s effect on the kinases PKC, CaMKII, and ERK, whereas the third part focuses on where we are in developing anti-amphetamine therapeutics. Thus, treatments are discussed that target DAT, VMAT2, PKC, CaMKII, and OCT3. As is generally true for the development of therapeutics for substance use disorder, there are multiple preclinically promising specific compounds against (meth)amphetamine, for which further development and clinical trials are badly needed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Alper KR, Lotsof HS, Kaplan CD (2008) The ibogaine medical subculture. J Ethnopharmacol 115:9–24

    Article  CAS  PubMed  Google Scholar 

  • Altshuler R, Gnegy M, Jutkiewicz E (2016) The protein kinase Cbeta inhibitor, enzastaurin, decreases amphetamine-stimulated behaviors in rats. FASEB J 30:1183–1188

    Google Scholar 

  • Anderson AL, Li SH, Markova D, Holmes TH, Chiang N, Kahn R, Campbell J, Dickerson DL, Galloway GP, Haning W, Roache JD, Stock C, Elkashef AM (2015) Bupropion for the treatment of methamphetamine dependence in non-daily users: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend 150:170–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Apel ED, Byford MF, Au D, Walsh KA, Storm DR (1990) Identification of the protein kinase C phosphorylation site in neuromodulin. Biochemistry 29:2330–2335

    Article  CAS  PubMed  Google Scholar 

  • Arnold EB, Molinoff PB, Rutledge CO (1977) The release of endogenous norepinephrine and dopamine from cerebral cortex by amphetamine. J Pharmacol Exp Ther 202:544–557

    CAS  PubMed  Google Scholar 

  • Avelar AJ, Juliano SA, Garris PA (2013) Amphetamine augments vesicular dopamine release in the dorsal and ventral striatum through different mechanisms. J Neurochem 125:373–385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baldessarini RJ, Vogt M (1971) The uptake and subcellular distribution of aromatic amines in the brain of the rat. J Neurochem 18:2519–2533

    Article  CAS  PubMed  Google Scholar 

  • Banks ML, Blough BE, Fennell TR, Snyder RW, Negus SS (2013a) Effects of phendimetrazine treatment on cocaine vs food choice and extended-access cocaine consumption in rhesus monkeys. Neuropsychopharmacology 38:2698–2707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banks ML, Blough BE, Negus SS (2013b) Interaction between behavioral and pharmacological treatment strategies to decrease cocaine choice in rhesus monkeys. Neuropsychopharmacology 38:395–404

    Article  CAS  PubMed  Google Scholar 

  • Banks ML, Smith DA, Blough BE (2016) Methamphetamine-like discriminative stimulus effects of bupropion and its two hydroxy metabolites in male rhesus monkeys. Behav Pharmacol 27:196–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beerepoot P, Lam VM, Salahpour A (2016) Pharmacological chaperones of the dopamine transporter rescue dopamine transporter deficiency syndrome mutations in heterologous cells. J Biol Chem 291:22053–22062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berfield JL, Wang LC, Reith ME (1999) Which form of dopamine is the substrate for the human dopamine transporter: the cationic or the uncharged species? J Biol Chem 274:4876–4882

    Article  CAS  PubMed  Google Scholar 

  • Bhat S, Hasenhuetl PS, Kasture A, El-Kasaby A, Baumann MH, Blough BE, Sucic S, Sandtner W, Freissmuth M (2017) Conformational state interactions provide clues to the pharmacochaperone potential of serotonin transporter partial substrates. J Biol Chem 292:16773–16786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brensilver M, Heinzerling KG, Shoptaw S (2013) Pharmacotherapy of amphetamine-type stimulant dependence: an update. Drug Alcohol Rev 32:449–460

    Article  PubMed  PubMed Central  Google Scholar 

  • Browman KE, Kantor L, Richardson S, Badiani A, Robinson TE, Gnegy ME (1998) Injection of the protein kinase C inhibitor Ro31-8220 into the nucleus accumbens attenuates the acute response to amphetamine: tissue and behavioral studies. Brain Res 814:112–119

    Article  CAS  PubMed  Google Scholar 

  • Brown TK, Alper K (2018) Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes. Am J Drug Alcohol Abuse 44:24–36

    Article  PubMed  Google Scholar 

  • Bulling S, Schicker K, Zhang YW, Steinkellner T, Stockner T, Gruber CW, Boehm S, Freissmuth M, Rudnick G, Sitte HH, Sandtner W (2012) The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters. J Biol Chem 287:18524–18534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Butcher SP, Fairbrother IS, Kelly JS, Arbuthnott GW (1988) Amphetamine-induced dopamine release in the rat striatum: an in vivo microdialysis study. J Neurochem 50:346–355

    Article  CAS  PubMed  Google Scholar 

  • Cadoni C, Pinna A, Russi G, Consolo S, Di Chiara G (1995) Role of vesicular dopamine in the in vivo stimulation of striatal dopamine transmission by amphetamine: evidence from microdialysis and Fos immunohistochemistry. Neuroscience 65:1027–1039

    Article  CAS  PubMed  Google Scholar 

  • Calipari ES, Ferris MJ (2013) Amphetamine mechanisms and actions at the dopamine terminal revisited. J Neurosci 33:8923–8925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cameron KN, Solis E Jr, Ruchala I, De Felice LJ, Eltit JM (2015) Amphetamine activates calcium channels through dopamine transporter-mediated depolarization. Cell Calcium 58:457–466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carlsson A, Fuxe K, Hamberger B, Lindqvist M (1966) Biochemical and histochemical studies on the effects of imipramine-like drugs and (+)-amphetamine on central and peripheral catecholamine neurons. Acta Physiol Scand 67:481–497

    Article  CAS  PubMed  Google Scholar 

  • Carpenter C, Sorenson RJ, Jin Y, Klossowski S, Cierpicki T, Gnegy M, Showalter HD (2016) Design and synthesis of triarylacrylonitrile analogues of tamoxifen with improved binding selectivity to protein kinase C. Bioorg Med Chem 24:5495–5504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carpenter C, Zestos AG, Altshuler R, Sorenson RJ, Guptaroy B, Showalter HD, Kennedy RT, Jutkiewicz E, Gnegy ME (2017) Direct and systemic administration of a CNS-permeant tamoxifen analog reduces amphetamine-induced dopamine release and reinforcing effects. Neuropsychopharmacology 42:1940–1949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carson DS, Taylor ER (2014) Commentary on Heinzerling et al. (2014): a growing methamphetamine dependence therapeutics graveyard. Addiction 109:1887–1888

    Article  PubMed  Google Scholar 

  • Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remiao F, Carvalho F, Bastos Mde L (2012) Toxicity of amphetamines: an update. Arch Toxicol 86:1167–1231

    Article  CAS  PubMed  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  CAS  PubMed  PubMed Central  Google Scholar 

  • Cervinski MA, Foster JD, Vaughan RA (2005) Psychoactive substrates stimulate dopamine transporter phosphorylation and down-regulation by cocaine-sensitive and protein kinase C-dependent mechanisms. J Biol Chem 280:40442–40449

    Article  CAS  PubMed  Google Scholar 

  • Challasivakanaka S, Zhen J, Smith ME, Reith MEA, Foster JD, Vaughan RA (2017) Dopamine transporter phosphorylation site threonine 53 is stimulated by amphetamines and regulates dopamine transport, efflux, and cocaine analog binding. J Biol Chem 292:19066–19075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen N, Reith ME (2004) Interaction between dopamine and its transporter: role of intracellular sodium ions and membrane potential. J Neurochem 89:750–765

    Article  CAS  PubMed  Google Scholar 

  • Chen N, Reith ME (2008) Substrates dissociate dopamine transporter oligomers. J Neurochem 105:910–920

    Article  CAS  PubMed  Google Scholar 

  • Chen N, Vaughan RA, Reith ME (2001) The role of conserved tryptophan and acidic residues in the human dopamine transporter as characterized by site-directed mutagenesis. J Neurochem 77:1116–1127

    Article  CAS  PubMed  Google Scholar 

  • Chen N, Rickey J, Reith ME (2003) Na+ stimulates binding of dopamine to the dopamine transporter in cells but not in cell-free preparations. J Neurochem 86:678–686

    Article  CAS  PubMed  Google Scholar 

  • Chen N, Rickey J, Berfield JL, Reith ME (2004a) Aspartate 345 of the dopamine transporter is critical for conformational changes in substrate translocation and cocaine binding. J Biol Chem 279:5508–5519

    Article  CAS  PubMed  Google Scholar 

  • Chen N, Zhen J, Reith ME (2004b) Mutation of Trp84 and Asp313 of the dopamine transporter reveals similar mode of binding interaction for GBR12909 and benztropine as opposed to cocaine. J Neurochem 89:853–864

    Article  CAS  PubMed  Google Scholar 

  • Chen R, Furman CA, Zhang M, Kim MN, RWt G, 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  CAS  PubMed  Google Scholar 

  • Chico LK, van Eldik LJ, Watterson DM (2009) Targeting protein kinases in central nervous system disorders. Nat Rev Drug Discov 8:892–909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiueh CC, Moore KE (1975) D-amphetamine-induced release of “newly synthesized” and “stored” dopamine from the caudate nucleus in vivo. J Pharmacol Exp Ther 192:642–653

    CAS  PubMed  Google Scholar 

  • Corera AT, Costentin J, Bonnet JJ (2000) Binding of uptake blockers to the neuronal dopamine transporter: further investigation about cationic and anionic requirements. Naunyn Schmiedeberg’s Arch Pharmacol 362:213–221

    Article  CAS  Google Scholar 

  • Covey DP, Juliano SA, Garris PA (2013) Amphetamine elicits opposing actions on readily releasable and reserve pools for dopamine. PLoS One 8:e60763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cubeddu LX, Lovenberg TW, Hoffman IS, Talmaciu RK (1989) Phorbol esters and D2-dopamine receptors. J Pharmacol Exp Ther 251:687–693

    CAS  PubMed  Google Scholar 

  • Czoty PW, Blough BE, Fennell TR, Snyder RW, Nader MA (2016) Attenuation of cocaine self-administration by chronic oral phendimetrazine in rhesus monkeys. Neuroscience 324:367–376

    Article  CAS  PubMed  Google Scholar 

  • Daberkow DP, Brown HD, Bunner KD, Kraniotis SA, Doellman MA, Ragozzino ME, Garris PA, Roitman MF (2013) Amphetamine paradoxically augments exocytotic dopamine release and phasic dopamine signals. J Neurosci 33:452–463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dwoskin LP, Crooks PA (2002) A novel mechanism of action and potential use for lobeline as a treatment for psychostimulant abuse. Biochem Pharmacol 63:89–98

    Article  CAS  PubMed  Google Scholar 

  • Edashige K, Sato EF, Akimaru K, Yoshioka T, Utsumi K (1991) Nonsteroidal antiestrogen suppresses protein kinase C – its inhibitory effect on interaction of substrate protein with membrane. Cell Struct Funct 16:273–281

    Article  CAS  PubMed  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  CAS  PubMed  PubMed Central  Google Scholar 

  • Einat H, Yuan P, Szabo ST, Dogra S, Manji HK (2007) Protein kinase C inhibition by tamoxifen antagonizes manic-like behavior in rats: implications for the development of novel therapeutics for bipolar disorder. Neuropsychobiology 55:123–131

    Article  CAS  PubMed  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  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • Floor E, Meng L (1996) Amphetamine releases dopamine from synaptic vesicles by dual mechanisms. Neurosci Lett 215:53–56

    Article  CAS  PubMed  Google Scholar 

  • Fog JU, Khoshbouei H, Holy M, Owens WA, Vaegter CB, Sen N, Nikandrova Y, Bowton E, McMahon DG, Colbran RJ, Daws LC, 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  CAS  PubMed  Google Scholar 

  • Fon EA, Pothos EN, Sun BC, Killeen N, Sulzer D, Edwards RH (1997) Vesicular transport regulates monoamine storage and release but is not essential for amphetamine action. Neuron 19:1271–1283

    Article  CAS  PubMed  Google Scholar 

  • Foster JD, Vaughan RA (2017) Phosphorylation mechanisms in dopamine transporter regulation. J Chem Neuroanat 83-84:10–18

    Article  CAS  PubMed  Google Scholar 

  • Foster JD, Pananusorn B, Vaughan RA (2002) Dopamine transporters are phosphorylated on N-terminal serines in rat striatum. J Biol Chem 277:25178–25186

    Article  CAS  PubMed  Google Scholar 

  • Foster JD, Yang JW, Moritz AE, Challasivakanaka S, Smith MA, Holy M, Wilebski K, Sitte HH, Vaughan RA (2012) Dopamine transporter phosphorylation site threonine 53 regulates substrate reuptake and amphetamine-stimulated efflux. J Biol Chem 287:29702–29712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Freyberg Z, Sonders MS, Aguilar JI, Hiranita T, Karam CS, Flores J, Pizzo AB, Zhang Y, Farino ZJ, Chen A, Martin CA, Kopajtic TA, Fei H, Hu G, Lin YY, Mosharov EV, McCabe BD, Freyberg R, Wimalasena K, Hsin LW, Sames D, Krantz DE, Katz JL, Sulzer D, Javitch JA (2016) Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain. Nat Commun 7:10652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fudala PJ, Iwamoto ET (1986) Further studies on nicotine-induced conditioned place preference in the rat. Pharmacol Biochem Behav 25:1041–1049

    Article  CAS  PubMed  Google Scholar 

  • Furman CA, Chen R, Guptaroy B, Zhang M, Holz RW, Gnegy M (2009) Dopamine and amphetamine rapidly increase dopamine transporter trafficking to the surface: live-cell imaging using total internal reflection fluorescence microscopy. J Neurosci 29:3328–3336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia-Pardo MP, Roger-Sanchez C, Rodriguez-Arias M, Minarro J, Aguilar MA (2016) Pharmacological modulation of protein kinases as a new approach to treat addiction to cocaine and opiates. Eur J Pharmacol 781:10–24

    Article  CAS  PubMed  Google Scholar 

  • Gasser PJ (2019) Roles for the uptake2 transporter OCT3 in regulation of dopaminergic neurotransmission and behavior. Neurochem Int 123:46–49

    Article  CAS  PubMed  Google Scholar 

  • German DC, McMillen BA, Sanghera MK, Saffer SI, Shore PA (1981) Effects of severe dopamine depletion on dopamine neuronal impulse flow and on tyrosine hydroxylase regulation. Brain Res Bull 6:131–134

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Giambalvo CT (2004) Mechanisms underlying the effects of amphetamine on particulate PKC activity. Synapse 51:128–139

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Gnegy ME, Khoshbouei H, Berg KA, 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  CAS  PubMed  Google Scholar 

  • Gonzalez AM, Walther D, Pazos A, Uhl GR (1994) Synaptic vesicular monoamine transporter expression: distribution and pharmacologic profile. Brain Res Mol Brain Res 22:219–226

    Article  CAS  PubMed  Google Scholar 

  • Goodwin JS, Larson GA, Swant J, Sen N, Javitch JA, Zahniser NR, De Felice LJ, Khoshbouei H (2009) Amphetamine and methamphetamine differentially affect dopamine transporters in vitro and in vivo. J Biol Chem 284:2978–2989

    Article  CAS  PubMed  PubMed Central  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 

  • Gulley JM, Zahniser NR (2003) Rapid regulation of dopamine transporter function by substrates, blockers and presynaptic receptor ligands. Eur J Pharmacol 479:139–152

    Article  CAS  PubMed  Google Scholar 

  • Gundimeda U, Chen Z-H, Gopalakrishna R (1996) Tamoxifen modulates protein kinase C via oxidative stress in estrogen receptor-negative breast cancer cells. J Biol Chem 271:13504–13514

    Article  CAS  PubMed  Google Scholar 

  • Hadlock GC, Nelson CC, Baucum AJ 2nd, Hanson GR, Fleckenstein AE (2011) Ex vivo identification of protein-protein interactions involving the dopamine transporter. J Neurosci Methods 196:303–307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamilton PJ, Belovich AN, Khelashvili G, Saunders C, Erreger K, Javitch JA, Sitte HH, Weinstein H, Matthies HJG, Galli A (2014) PIP2 regulates psychostimulant behaviors through its interaction with a membrane protein. Nat Chem Biol 10:582–589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harrod SB, Dwoskin LP, Crooks PA, Klebaur JE, Bardo MT (2001) Lobeline attenuates d-methamphetamine self-administration in rats. J Pharmacol Exp Ther 298:172–179

    CAS  PubMed  Google Scholar 

  • Harrod SB, Dwoskin LP, Green TA, Gehrke BJ, Bardo MT (2003) Lobeline does not serve as a reinforcer in rats. Psychopharmacology 165:397–404

    Article  CAS  PubMed  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 98:10055–10060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heikkila RE, Orlansky H, Cohen G (1975) Studies on the distinction between uptake inhibition and release of (3H)dopamine in rat brain tissue slices. Biochem Pharmacol 24:847–852

    Article  CAS  PubMed  Google Scholar 

  • Heinzerling KG, Swanson AN, Hall TM, Yi Y, Wu Y, Shoptaw SJ (2014) Randomized, placebo-controlled trial of bupropion in methamphetamine-dependent participants with less than daily methamphetamine use. Addiction 109:1878–1886

    Article  PubMed  PubMed Central  Google Scholar 

  • Herman M, Nagler SH (1954) Psychoses due to amphetamine. J Nerv Ment Dis 120:268–272

    Article  CAS  PubMed  Google Scholar 

  • Holz RW, Coyle JT (1974) The effects of various salts, temperature, and the alkaloids veratridine and batrachotoxin on the uptake of [3H] dopamine into synaptosomes from rat striatum. Mol Pharmacol 10:746–758

    CAS  Google Scholar 

  • Horton RE, Apple DM, Owens WA, Baganz NL, Cano S, Mitchell NC, Vitela M, Gould GG, Koek W, Daws LC (2013) Decynium-22 enhances SSRI-induced antidepressant-like effects in mice: uncovering novel targets to treat depression. J Neurosci 33:10534–10543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Howell LL, Negus SS (2014) Monoamine transporter inhibitors and substrates as treatments for stimulant abuse. Adv Pharmacol 69:129–176

    Article  CAS  PubMed  PubMed Central  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  CAS  PubMed  Google Scholar 

  • Hurd YL, Ungerstedt U (1989) In vivo neurochemical profile of dopamine uptake inhibitors and releasers in rat caudate-putamen. Eur J Pharmacol 166:251–260

    Article  CAS  PubMed  Google Scholar 

  • Iversen L (2006) Neurotransmitter transporters and their impact on the development of psychopharmacology. Br J Pharmacol 147(Suppl 1):S82–S88

    CAS  PubMed  PubMed Central  Google Scholar 

  • Iwata S, Hewlett GH, Ferrell ST, Czernik AJ, Meiri KF, Gnegy ME (1996) Increased in vivo phosphorylation state of neuromodulin and synapsin I in striatum from rats treated with repeated amphetamine. J Pharmacol Exp Ther 278:1428–1434

    CAS  PubMed  Google Scholar 

  • Iwata S, Hewlett GH, Gnegy ME (1997) Amphetamine increases the phosphorylation of neuromodulin and synapsin I in rat striatal synaptosomes. Synapse 26:281–291

    Article  CAS  PubMed  Google Scholar 

  • Jacobs MT, Zhang YW, Campbell SD, Rudnick G (2007) Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter. J Biol Chem 282:29441–29447

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Johnson J, Milner G (1966) Psychiatric complications of amphetamine substances. Acta Psychiatr Scand 42:252–263

    Article  CAS  PubMed  Google Scholar 

  • Johnson LA, Furman CA, Zhang M, Guptaroy B, Gnegy ME (2005a) Rapid delivery of the dopamine transporter to the plasmalemmal membrane upon amphetamine stimulation. Neuropharmacology 49:750–758

    Article  CAS  PubMed  Google Scholar 

  • Johnson LA, Guptaroy B, Lund D, Shamban S, Gnegy ME (2005b) Regulation of amphetamine-stimulated dopamine efflux by protein kinase C beta. J Biol Chem 280:10914–10919

    Article  CAS  PubMed  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

    Article  CAS  PubMed  PubMed Central  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  CAS  PubMed  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  CAS  PubMed  PubMed Central  Google Scholar 

  • Kangiser MM, Dwoskin LP, Zheng G, Crooks PA, Stairs DJ (2018) Varenicline and GZ-793A differentially decrease methamphetamine self-administration under a multiple schedule of reinforcement in rats. Behav Pharmacol 29:87–97

    Article  CAS  PubMed  PubMed Central  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

    CAS  PubMed  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kantor L, Hewlett GH, 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

    CAS  PubMed  Google Scholar 

  • Karam CS, Sen N, Javitch JA (2017) Phospho-specific antibodies targeting the amino terminus of the human dopamine transporter. J Chem Neuroanat 83-84:91–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katz JL, Izenwasser S, Kline RH, Allen AC, Newman AH (1999) Novel 3alpha-diphenylmethoxytropane analogs: selective dopamine uptake inhibitors with behavioral effects distinct from those of cocaine. J Pharmacol Exp Ther 288:302–315

    CAS  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 278:12070–12077

    Article  CAS  PubMed  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  PubMed Central  Google Scholar 

  • King M, Hosmer H, Dresbach M (1928) Physiological reactions induced by alpha-lobeline. I. Intravenous injections during anesthesia and certain other forms of depression. J Pharmacol Exp Ther 32:241–272

    CAS  Google Scholar 

  • Krishnamurthy H, Gouaux E (2012) X-ray structures of LeuT in substrate-free outward-open and apo inward-open states. Nature 481:469–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuhr WG, Ewing AG, Near JA, Wightman RM (1985) Amphetamine attenuates the stimulated release of dopamine in vivo. J Pharmacol Exp Ther 232:388–394

    CAS  PubMed  Google Scholar 

  • Lee AM, Messing RO (2008) Protein kinases and addiction. Ann N Y Acad Sci 1141:22–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee NK, Jenner L, Harney A, Cameron J (2018a) Pharmacotherapy for amphetamine dependence: a systematic review. Drug Alcohol Depend 191:309–337

    Article  CAS  PubMed  Google Scholar 

  • Lee NR, Zheng G, Crooks PA, Bardo MT, Dwoskin LP (2018b) New scaffold for lead compounds to treat methamphetamine use disorders. AAPS J 20:29

    Article  PubMed  CAS  Google Scholar 

  • Lentzen H, Philippu A (1981) Physico-chemical properties of phenethylamines and their uptake into synaptic vesicles of the caudate nucleus. Biochem Pharmacol 30:1759–1764

    Article  CAS  PubMed  Google Scholar 

  • Leviel V (2011) Dopamine release mediated by the dopamine transporter, facts and consequences. J Neurochem 118:475–489

    Article  CAS  PubMed  Google Scholar 

  • Li LB, Reith ME (1999) Modeling of the interaction of Na+ and K+ with the binding of dopamine and [3H]WIN 35,428 to the human dopamine transporter. J Neurochem 72:1095–1109

    Article  CAS  PubMed  Google Scholar 

  • Li LB, Reith ME (2000) Interaction of Na+, K+, and Cl- with the binding of amphetamine, octopamine, and tyramine to the human dopamine transporter. J Neurochem 74:1538–1552

    Article  CAS  PubMed  Google Scholar 

  • Li LB, Cui XN, Reith MA (2002) Is Na(+) required for the binding of dopamine, amphetamine, tyramine, and octopamine to the human dopamine transporter? Naunyn Schmiedeberg’s Arch Pharmacol 365:303–311

    Article  CAS  Google Scholar 

  • Li Y, Cheng SY, Chen N, Reith ME (2010) Interrelation of dopamine transporter oligomerization and surface presence as studied with mutant transporter proteins and amphetamine. J Neurochem 114:873–885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liang NY, Rutledge CO (1982) Evidence for carrier-mediated efflux of dopamine from corpus striatum. Biochem Pharmacol 31:2479–2484

    Article  CAS  PubMed  Google Scholar 

  • Lien EA, Solheim E, Ueland PM (1991) Distribution of tamoxifen and its metabolites in rat and human tissues during steady-state treatment. Cancer Res 51:4837–4844

    CAS  PubMed  Google Scholar 

  • Lightman SL, Iversen LL (1969) The role of uptake2 in the extraneuronal metabolism of catecholamines in the isolated rat heart. Br J Pharmacol 37:638–649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin M, Sambo D, Khoshbouei H (2016) Methamphetamine regulation of firing activity of dopamine neurons. J Neurosci 36:10376–10391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loland CJ, Mereu M, Okunola OM, Cao J, Prisinzano TE, Mazier S, Kopajtic T, Shi L, Katz JL, Tanda G, Newman AH (2012) R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. Biol Psychiatry 72:405–413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loweth JA, Baker LK, Guptaa T, Guillory AM, Vezina P (2008) Inhibition of CaMKII in the nucleus accumbens shell decreases enhanced amphetamine intake in sensitized rats. Neurosci Lett 444:157–160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loweth JA, Svoboda R, Austin JD, Guillory AM, Vezina P (2009) The PKC inhibitor Ro31-8220 blocks acute amphetamine-induced dopamine overflow in the nucleus accumbens. Neurosci Lett 455:88–92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loweth JA, Singer BF, Baker LK, Wilke G, Inamine H, Bubula N, Alexander JK, Carlezon WA Jr, Neve RL, Vezina P (2010) Transient overexpression of alpha-Ca2+/calmodulin-dependent protein kinase II in the nucleus accumbens shell enhances behavioral responding to amphetamine. J Neurosci 30:939–949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luderman KD, Chen R, Ferris MJ, Jones SR, Gnegy ME (2015) Protein kinase C beta regulates the D(2)-like dopamine autoreceptor. Neuropharmacology 89:335–341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malcolm E, Carroll FI, Blough B, Damaj MI, Shoaib M (2015) Examination of the metabolite hydroxybupropion in the reinforcing and aversive stimulus effects of nicotine in rats. Psychopharmacology 232:2763–2771

    Article  CAS  PubMed  Google Scholar 

  • Malinauskaite L, Quick M, Reinhard L, Lyons JA, Yano H, Javitch JA, Nissen P (2014) A mechanism for intracellular release of Na+ by neurotransmitter/sodium symporters. Nat Struct Mol Biol 21:1006–1012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mayer FP, Luf A, Nagy C, Holy M, Schmid R, Freissmuth M, Sitte HH (2017) Application of a combined approach to identify new psychoactive street drugs and decipher their mechanisms at monoamine transporters. Curr Top Behav Neurosci 32:333–350

    Article  CAS  PubMed  Google Scholar 

  • Mayer FP, Schmid D, Owens WA, Gould GG, Apuschkin M, Kudlacek O, Salzer I, Boehm S, Chiba P, Williams PH, Wu HH, Gether U, Koek W, Daws LC, Sitte HH (2018) An unsuspected role for organic cation transporter 3 in the actions of amphetamine. Neuropsychopharmacology 43:2408–2417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meinild AK, Sitte HH, Gether U (2004) Zinc potentiates an uncoupled anion conductance associated with the dopamine transporter. J Biol Chem 279:49671–49679

    Article  CAS  PubMed  Google Scholar 

  • Meiri KF, Bickerstaff LE, Schwob JE (1991) Monoclonal antibodies show that kinase C phosphorylation of GAP-43 during axonogenesis is both spatially and temporally restricted in vivo. J Cell Biol 112:991–1005

    Article  CAS  PubMed  Google Scholar 

  • Meyer AC, Horton DB, Neugebauer NM, Wooters TE, Nickell JR, Dwoskin LP, Bardo MT (2011) Tetrabenazine inhibition of monoamine uptake and methamphetamine behavioral effects: locomotor activity, drug discrimination and self-administration. Neuropharmacology 61:849–856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mikelman S, Mardirossian N, Gnegy ME (2017a) Tamoxifen and amphetamine abuse: are there therapeutic possibilities? J Chem Neuroanat 83-84:50–58

    Article  CAS  PubMed  Google Scholar 

  • Mikelman SR, Guptaroy B, Gnegy ME (2017b) Tamoxifen and its active metabolites inhibit dopamine transporter function independently of the estrogen receptors. J Neurochem 141:31–36

    Article  CAS  PubMed  Google Scholar 

  • Mikelman SR, Guptaroy B, Schmitt KC, Jones KT, Zhen J, Reith MEA, Gnegy ME (2018) Tamoxifen directly interacts with the dopamine transporter. J Pharmacol Exp Ther 367:119–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mundorf ML, Hochstetler SE, Wightman RM (1999) Amine weak bases disrupt vesicular storage and promote exocytosis in chromaffin cells. J Neurochem 73:2397–2405

    Article  CAS  PubMed  Google Scholar 

  • Namkung Y, Sibley DR (2004) Protein kinase C mediates phosphorylation, desensitization, and trafficking of the D2 dopamine receptor. J Biol Chem 279:49533–49541

    Article  CAS  PubMed  Google Scholar 

  • Nickell JR, Siripurapu KB, Vartak A, Crooks PA, Dwoskin LP (2014) The vesicular monoamine transporter-2: an important pharmacological target for the discovery of novel therapeutics to treat methamphetamine abuse. Adv Pharmacol 69:71–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niddam R, Arbilla S, Scatton B, Dennis T, Langer SZ (1985) Amphetamine induced release of endogenous dopamine in vitro is not reduced following pretreatment with reserpine. Naunyn Schmiedeberg’s Arch Pharmacol 329:123–127

    Article  CAS  Google Scholar 

  • Nimitvilai S, McElvain MA, Brodie MS (2013) Reversal of dopamine D2 agonist-induced inhibition of ventral tegmental area neurons by Gq-linked neurotransmitters is dependent on protein kinase C, G protein-coupled receptor kinase, and dynamin. J Pharmacol Exp Ther 344:253–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nomikos GG, Damsma G, Wenkstern D, Fibiger HC (1990) In vivo characterization of locally applied dopamine uptake inhibitors by striatal microdialysis. Synapse 6:106–112

    Article  CAS  PubMed  Google Scholar 

  • O’Brian CA, Liskamp RM, Solomon DH, Weinstein IB (1985) Inhibition of protein kinase C by tamoxifen. Cancer Res 45:2462–2465

    PubMed  Google Scholar 

  • Ofori S, Bretton C, Hof P, Schorderet M (1986) Investigation of dopamine content, synthesis, and release in the rabbit retina in vitro: I. Effects of dopamine precursors, reserpine, amphetamine, and L-DOPA decarboxylase and monoamine oxidase inhibitors. J Neurochem 47:1199–1206

    Article  CAS  PubMed  Google Scholar 

  • Pariser JJ, Partilla JS, Dersch CM, Ananthan S, Rothman RB (2008) Studies of the biogenic amine transporters. 12. Identification of novel partial inhibitors of amphetamine-induced dopamine release. J Pharmacol Exp Ther 326:286–295

    Article  CAS  PubMed  Google Scholar 

  • Parker EM, Cubeddu LX (1986) Effects of d-amphetamine and dopamine synthesis inhibitors on dopamine and acetylcholine neurotransmission in the striatum. I. Release in the absence of vesicular transmitter stores. J Pharmacol Exp Ther 237:179–192

    CAS  PubMed  Google Scholar 

  • Partilla JS, Dempsey AG, Nagpal AS, Blough BE, Baumann MH, Rothman RB (2006) Interaction of amphetamines and related compounds at the vesicular monoamine transporter. J Pharmacol Exp Ther 319:237–246

    Article  CAS  PubMed  Google Scholar 

  • Patel J, Mooslehner KA, Chan PM, Emson PC, Stamford JA (2003) Presynaptic control of striatal dopamine neurotransmission in adult vesicular monoamine transporter 2 (VMAT2) mutant mice. J Neurochem 85:898–910

    Article  CAS  PubMed  Google Scholar 

  • Penmatsa A, Wang KH, Gouaux E (2015) X-ray structures of Drosophila dopamine transporter in complex with nisoxetine and reboxetine. Nat Struct Mol Biol 22:506–508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peter D, Jimenez J, Liu Y, Kim J, Edwards RH (1994) The chromaffin granule and synaptic vesicle amine transporters differ in substrate recognition and sensitivity to inhibitors. J Biol Chem 269:7231–7237

    CAS  PubMed  Google Scholar 

  • Pierce RC, Kalivas PW (1997) Repeated cocaine modifies the mechanism by which amphetamine releases dopamine. J Neurosci 17:3254–3261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pierce RC, Quick EA, Reeder DC, Morgan ZR, Kalivas PW (1998) Calcium-mediated second messengers modulate the expression of behavioral sensitization to cocaine. J Pharmacol Exp Ther 286:1171–1176

    CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • Pizzo AB, Karam CS, Zhang Y, Yano H, Freyberg RJ, Karam DS, Freyberg Z, Yamamoto A, McCabe BD, Javitch JA (2013) The membrane raft protein Flotillin-1 is essential in dopamine neurons for amphetamine-induced behavior in Drosophila. Mol Psychiatry 18:824–833

    Article  CAS  PubMed  Google Scholar 

  • Pizzo AB, Karam CS, Zhang Y, Ma CL, McCabe BD, Javitch JA (2014) Amphetamine-induced behavior requires CaMKII-dependent dopamine transporter phosphorylation. Mol Psychiatry 19:279–281

    Article  CAS  PubMed  Google Scholar 

  • Raiteri M, Bertollini A, del Carmine R, Levi G (1976) Release of biogenic amines from isolated nerve endings. Adv Exp Med Biol 69:319–335

    Article  CAS  PubMed  Google Scholar 

  • Ramamoorthy S, Shippenberg TS, Jayanthi LD (2011) Regulation of monoamine transporters: role of transporter phosphorylation. Pharmacol Ther 129:220–238

    Article  CAS  PubMed  Google Scholar 

  • Rastedt DE, Vaughan RA, Foster JD (2017) Palmitoylation mechanisms in dopamine transporter regulation. J Chem Neuroanat 83-84:3–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL (2015) Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter. Drug Alcohol Depend 147:1–19

    Article  CAS  PubMed  Google Scholar 

  • Richards TL, Zahniser NR (2009) Rapid substrate-induced down-regulation in function and surface localization of dopamine transporters: rat dorsal striatum versus nucleus accumbens. J Neurochem 108:1575–1584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rickhag M, Owens WA, Winkler MT, Strandfelt KN, Rathje M, Sorensen G, Andresen B, Madsen KL, Jorgensen TN, Wortwein G, Woldbye DP, Sitte H, Daws LC, Gether U (2013) Membrane-permeable C-terminal dopamine transporter peptides attenuate amphetamine-evoked dopamine release. J Biol Chem 288:27534–27544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robinson TE, Becker JB (1986) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res 396:157–198

    Article  CAS  PubMed  Google Scholar 

  • Ross SB, Renyi AL (1966) Uptake of tritiated tyramine and (+) amphetamine by mouse heart slices. J Pharm Pharmacol 18:756–757

    Article  CAS  PubMed  Google Scholar 

  • Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (2001) Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 39:32–41

    Article  CAS  PubMed  Google Scholar 

  • Rothman RB, Dersch CM, Ananthan S, Partilla JS (2009) Studies of the biogenic amine transporters. 13. Identification of “agonist” and “antagonist” allosteric modulators of amphetamine-induced dopamine release. J Pharmacol Exp Ther 329:718–728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rothman RB, Partilla JS, Baumann MH, Lightfoot-Siordia C, Blough BE (2012) Studies of the biogenic amine transporters. 14. Identification of low-efficacy “partial” substrates for the biogenic amine transporters. J Pharmacol Exp Ther 341:251–262

    Article  CAS  PubMed  PubMed Central  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  CAS  PubMed  Google Scholar 

  • Sabol KE, Seiden LS (1998) Reserpine attenuates D-amphetamine and MDMA-induced transmitter release in vivo: a consideration of dose, core temperature and dopamine synthesis. Brain Res 806:69–78

    Article  CAS  PubMed  Google Scholar 

  • Sambo DO, Lin M, Owens A, Lebowitz JJ, Richardson B, Jagnarine DA, Shetty M, Rodriquez M, Alonge T, Ali M, Katz J, Yan L, Febo M, Henry LK, Bruijnzeel AW, Daws L, Khoshbouei H (2017) The sigma-1 receptor modulates methamphetamine dysregulation of dopamine neurotransmission. Nat Commun 8:2228

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schmitt KC, Reith ME (2010) Regulation of the dopamine transporter: aspects relevant to psychostimulant drugs of abuse. Ann N Y Acad Sci 1187:316–340

    Article  CAS  PubMed  Google Scholar 

  • Schmitt KC, Reith ME (2011) The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors. PLoS One 6:e25790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmitt KC, Zhen J, Kharkar P, Mishra M, Chen N, Dutta AK, Reith ME (2008) Interaction of cocaine-, benztropine-, and GBR12909-like compounds with wild-type and mutant human dopamine transporters: molecular features that differentially determine antagonist-binding properties. J Neurochem 107:928–940

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schmitz Y, Lee CJ, Schmauss C, Gonon F, Sulzer D (2001) Amphetamine distorts stimulation-dependent dopamine overflow: effects on D2 autoreceptors, transporters, and synaptic vesicle stores. J Neurosci 21:5916–5924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwartzberg L, Hermann R, Flinn I, Flora D, Hsi ED, Hamid O, Shi P, Lin BK, Myrand SP, Nguyen TS, Dreyling M (2014) Open-label, single-arm, phase II study of enzastaurin in patients with follicular lymphoma. Br J Haematol 166:91–97

    Article  CAS  PubMed  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

    Article  CAS  PubMed  Google Scholar 

  • Shelly W, Draper MW, Krishnan V, Wong M, Jaffe RB (2008) Selective estrogen receptor modulators: an update on recent clinical findings. Obstet Gynecol Surv 63:163–181

    PubMed  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  CAS  PubMed  PubMed Central  Google Scholar 

  • Siciliano CA, Calipari ES, Ferris MJ, Jones SR (2014) Biphasic mechanisms of amphetamine action at the dopamine terminal. J Neurosci 34:5575–5582

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Singh SK, Yamashita A, Gouaux E (2007) Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. Nature 448:952–956

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sitte HH, Freissmuth M (2010) The reverse operation of Na(+)/Cl(-)-coupled neurotransmitter transporters – why amphetamines take two to tango. J Neurochem 112:340–355

    Article  CAS  PubMed  Google Scholar 

  • Sitte HH, Freissmuth M (2015) Amphetamines, new psychoactive drugs and the monoamine transporter cycle. Trends Pharmacol Sci 36:41–50

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Smith CB (1963) Enhancement by reserpine and alpha-methyl dopa of the effects of D-amphetamine upon the locomotor activity of mice. J Pharmacol Exp Ther 142:343–350

    CAS  PubMed  Google Scholar 

  • Solis E Jr, Suyama JA, Lazenka MF, DeFelice LJ, Negus SS, Blough BE, Banks ML (2016) Dissociable effects of the prodrug phendimetrazine and its metabolite phenmetrazine at dopamine transporters. Sci Rep 6:31385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sonders MS, Zhu SJ, Zahniser NR, Kavanaugh MP, Amara SG (1997) Multiple ionic conductances of the human dopamine transporter: the actions of dopamine and psychostimulants. J Neurosci 17:960–974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sorkina T, Doolen S, Galperin E, Zahniser NR, Sorkin A (2003) Oligomerization of dopamine transporters visualized in living cells by fluorescence resonance energy transfer microscopy. J Biol Chem 278:28274–28283

    Article  CAS  PubMed  Google Scholar 

  • Steinkellner T, Yang JW, Montgomery TR, Chen WQ, Winkler MT, Sucic S, Lubec G, Freissmuth M, Elgersma Y, Sitte HH, Kudlacek O (2012) Ca(2+)/calmodulin-dependent protein kinase IIalpha (alphaCaMKII) controls the activity of the dopamine transporter: implications for Angelman syndrome. J Biol Chem 287:29627–29635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stolerman IP, Garcha HS, Mirza NR (1995) Dissociations between the locomotor stimulant and depressant effects of nicotinic agonists in rats. Psychopharmacology 117:430–437

    Article  CAS  PubMed  Google Scholar 

  • Stolzenberg S, Quick M, Zhao C, Gotfryd K, Khelashvili G, Gether U, Loland CJ, Javitch JA, Noskov S, Weinstein H, Shi L (2015) Mechanism of the association between Na+ binding and conformations at the intracellular gate in neurotransmitter: sodium symporters. J Biol Chem 290:13992–14003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su HD, Mazzei GJ, Vogler WR, Kuo JF (1985) Effect of tamoxifen, a nonsteroidal antiestrogen, on phospholipid/calcium-dependent protein kinase and phosphorylation of its endogenous substrate proteins from the rat brain and ovary. Biochem Pharmacol 34:3649–3653

    Article  CAS  PubMed  Google Scholar 

  • Sulzer D (2011) How addictive drugs disrupt presynaptic dopamine neurotransmission. Neuron 69:628–649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sulzer D, Chen TK, Lau YY, Kristensen H, Rayport S, Ewing A (1995) Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J Neurosci 15:4102–4108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Teng L, Crooks PA, Dwoskin LP (1998) Lobeline displaces [3H]dihydrotetrabenazine binding and releases [3H]dopamine from rat striatal synaptic vesicles: comparison with d-amphetamine. J Neurochem 71:258–265

    Article  CAS  PubMed  Google Scholar 

  • Thoenen H, Hurlimann A, Haefely W (1968) Mechanism of amphetamine accumulation in the isolated perfused heart of the rat. J Pharm Pharmacol 20:1–11

    Article  CAS  PubMed  Google Scholar 

  • Vaughan RA, Huff RA, Uhl GR, Kuhar MJ (1997) Protein kinase C-mediated phosphorylation and functional regulation of dopamine transporters in striatal synaptosomes. J Biol Chem 272:15541–15546

    Article  CAS  PubMed  Google Scholar 

  • Vezina P (2004) Sensitization of midbrain dopamine neuron reactivity and the self-administration of psychomotor stimulant drugs. Neurosci Biobehav Rev 27:827–839

    Article  CAS  PubMed  Google Scholar 

  • Vezina P, Lorrain DS, Arnold GM, Austin JD, Suto N (2002) Sensitization of midbrain dopamine neuron reactivity promotes the pursuit of amphetamine. J Neurosci 22:4654–4662

    Article  CAS  PubMed  PubMed Central  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

    CAS  PubMed  Google Scholar 

  • Wallis GG, Mc HJ, Scott OC (1949) Acute psychosis caused by dextro-amphetamine. Br Med J 2:1394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang YM, Gainetdinov RR, Fumagalli F, Xu F, Jones SR, Bock CB, Miller GW, Wightman RM, Caron MG (1997) Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine. Neuron 19:1285–1296

    Article  CAS  PubMed  Google Scholar 

  • Wang KH, Penmatsa A, Gouaux E (2015) Neurotransmitter and psychostimulant recognition by the dopamine transporter. Nature 521:322–327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Q, Bubula N, Brown J, Wang Y, Kondev V, Vezina P (2016) PKC phosphorylates residues in the N-terminal of the DA transporter to regulate amphetamine-induced DA efflux. Neurosci Lett 622:78–82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weissman A, Koe BK, Tenen SS (1966) Antiamphetamine effects following inhibition of tyrosine hydroxylase. J Pharmacol Exp Ther 151:339–352

    CAS  PubMed  Google Scholar 

  • Wieczorek WJ, Kruk ZL (1994) Differential action of (+)-amphetamine on electrically evoked dopamine overflow in rat brain slices containing corpus striatum and nucleus accumbens. Br J Pharmacol 111:829–836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wise RA, Bozarth MA (1985) Brain mechanisms of drug reward and euphoria. Psychiatr Med 3:445–460

    CAS  PubMed  Google Scholar 

  • Xu C, Coffey LL, Reith ME (1995) Translocation of dopamine and binding of 2 beta-carbomethoxy-3 beta-(4-fluorophenyl) tropane (WIN 35,428) measured under identical conditions in rat striatal synaptosomal preparations. Inhibition by various blockers. Biochem Pharmacol 49:339–350

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Zahniser NR, Sorkin A (2009) Trafficking of dopamine transporters in psychostimulant actions. Semin Cell Dev Biol 20:411–417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zarate CA, Manji HK (2009) Protein kinase C inhibitors: rationale for use and potential in the treatment of bipolar disorder. CNS Drugs 23:569–582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zestos AG, Mikelman SR, Kennedy RT, Gnegy ME (2016) PKCbeta inhibitors attenuate amphetamine-stimulated dopamine efflux. ACS Chem Neurosci 7:757–766

    Article  CAS  PubMed  Google Scholar 

  • Zestos AG, Carpenter C, Kim Y, Low MJ, Kennedy RT, Gnegy ME (2019) Ruboxistaurin reduces cocaine-stimulated increases in extracellular dopamine by modifying dopamine-autoreceptor activity. ACS Chem Neurosci 10:1960–1969

    Article  CAS  PubMed  Google Scholar 

  • Zetterstrom T, Sharp T, Collin AK, Ungerstedt U (1988) In vivo measurement of extracellular dopamine and DOPAC in rat striatum after various dopamine-releasing drugs; implications for the origin of extracellular DOPAC. Eur J Pharmacol 148:327–334

    Article  CAS  PubMed  Google Scholar 

  • Zhou Z, Zhen J, Karpowich NK, Goetz RM, Law CJ, Reith ME, Wang DN (2007) LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science 317:1390–1393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu HJ, Appel DI, Grundemann D, Markowitz JS (2010) Interaction of organic cation transporter 3 (SLC22A3) and amphetamine. J Neurochem 114:142–149

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zimanyi I, Lajtha A, Reith ME (1989) Comparison of characteristics of dopamine uptake and mazindol binding in mouse striatum. Naunyn Schmiedeberg’s Arch Pharmacol 340:626–632

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The most recent work by the authors described in this review was supported by NIH DA 019676 (MEAR) and R01DA011697 (MEG). We are grateful for the input given on Sect. 4.1 by Kyle C. Schmitt.

Author information

Authors and Affiliations

  1. Department of Psychiatry, New York University School of Medicine, New York, NY, USA

    Maarten E. A. Reith

  2. Department of Pharmacology, University of Michigan School of Medicine, Ann Arbor, MI, USA

    Margaret E. Gnegy

Authors
  1. Maarten E. A. Reith
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Margaret E. Gnegy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maarten E. A. Reith .

Editor information

Editors and Affiliations

  1. Wake Forest School of Medicine, Winston-Salem, NC, USA

    Michael A. Nader

  2. Addiction Institute of Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Yasmin L. Hurd

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Reith, M.E.A., Gnegy, M.E. (2019). Molecular Mechanisms of Amphetamines. In: Nader, M., Hurd, Y. (eds) Substance Use Disorders. Handbook of Experimental Pharmacology, vol 258. Springer, Cham. https://doi.org/10.1007/164_2019_251

Download citation

Publish with us

Policies and ethics

Search

Navigation