Dopamine transporter explained

The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the SLC6A3 gene (also known as DAT1), that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.[1] DAT is implicated in a number of dopamine-related disorders, including attention deficit hyperactivity disorder, bipolar disorder, clinical depression, eating disorders, and substance use disorders. The gene that encodes the DAT protein is located on chromosome 5, consists of 15 coding exons, and is roughly 64 kbp long. Evidence for the associations between DAT and dopamine related disorders has come from a type of genetic polymorphism, known as a variable number tandem repeat, in the SLC6A3 gene, which influences the amount of protein expressed.[2]

Function

DAT is an integral membrane protein that removes dopamine from the synaptic cleft and deposits it into surrounding cells, thus terminating the signal of the neurotransmitter. Dopamine underlies several aspects of cognition, including reward, and DAT facilitates regulation of that signal.[3]

Mechanism

DAT is a symporter that moves dopamine across the cell membrane by coupling the movement to the energetically-favorable movement of sodium ions moving from high to low concentration into the cell. DAT function requires the sequential binding and co-transport of two Na+ ions and one Cl− ion with the dopamine substrate. The driving force for DAT-mediated dopamine reuptake is the ion concentration gradient generated by the plasma membrane Na+/K+ ATPase.[4]

In the most widely accepted model for monoamine transporter function, sodium ions must bind to the extracellular domain of the transporter before dopamine can bind. Once dopamine binds, the protein undergoes a conformational change, which allows both sodium and dopamine to unbind on the intracellular side of the membrane.[5]

Studies using electrophysiology and radioactive-labeled dopamine have confirmed that the dopamine transporter is similar to other monoamine transporters in that one molecule of neurotransmitter can be transported across the membrane with one or two sodium ions. Chloride ions are also needed to prevent a buildup of positive charge. These studies have also shown that transport rate and direction is totally dependent on the sodium gradient.[6]

Because of the tight coupling of the membrane potential and the sodium gradient, activity-induced changes in membrane polarity can dramatically influence transport rates. In addition, the transporter may contribute to dopamine release when the neuron depolarizes.[6]

DAT–Cav coupling

Preliminary evidence suggests that the dopamine transporter couples to L-type voltage-gated calcium channels (particularly Cav1.2 and Cav1.3), which are expressed in virtually all dopamine neurons.[7] As a result of DAT–Cav coupling, DAT substrates that produce depolarizing currents through the transporter are able to open calcium channels that are coupled to the transporter, resulting in a calcium influx in dopamine neurons. This calcium influx is believed to induce CAMKII-mediated phosphorylation of the dopamine transporter as a downstream effect; since DAT phosphorylation by CAMKII results in dopamine efflux in vivo, activation of transporter-coupled calcium channels is a potential mechanism by which certain drugs (e.g., amphetamine) trigger neurotransmitter release.

Protein structure

The initial determination of the membrane topology of DAT was based upon hydrophobic sequence analysis and sequence similarities with the GABA transporter. These methods predicted twelve transmembrane domains (TMD) with a large extracellular loop between the third and fourth TMDs.[8] Further characterization of this protein used proteases, which digest proteins into smaller fragments, and glycosylation, which occurs only on extracellular loops, and largely verified the initial predictions of membrane topology.[9] The exact structure of the Drosophila melanogaster dopamine transporter (dDAT) was elucidated in 2013 by X-ray crystallography.[10]

Location and distribution

Regional distribution of DAT has been found in areas of the brain with established dopaminergic circuitry, including the nigrostriatal, mesolimbic, and mesocortical pathways.[11] The nuclei that make up these pathways have distinct patterns of expression. Gene expression patterns in the adult mouse show high expression in the substantia nigra pars compacta.[12]

DAT in the mesocortical pathway, labeled with radioactive antibodies, was found to be enriched in dendrites and cell bodies of neurons in the substantia nigra pars compacta and ventral tegmental area. This pattern makes sense for a protein that regulates dopamine levels in the synapse.

Staining in the striatum and nucleus accumbens of the mesolimbic pathway was dense and heterogeneous. In the striatum, DAT is localized in the plasma membrane of axon terminals. Double immunocytochemistry demonstrated DAT colocalization with two other markers of nigrostriatal terminals, tyrosine hydroxylase and D2 dopamine receptors. The latter was thus demonstrated to be an autoreceptor on cells that release dopamine. TAAR1 is a presynaptic intracellular receptor that is also colocalized with DAT and which has the opposite effect of the D2 autoreceptor when activated;[13] i.e., it internalizes dopamine transporters and induces efflux through reversed transporter function via PKA and PKC signaling.

Surprisingly, DAT was not identified within any synaptic active zones. These results suggest that striatal dopamine reuptake may occur outside of synaptic specializations once dopamine diffuses from the synaptic cleft.

In the substantia nigra, DAT is localized to axonal and dendritic (i.e., pre- and post-synaptic) plasma membranes.[14]

Within the perikarya of pars compacta neurons, DAT was localized primarily to rough and smooth endoplasmic reticulum, Golgi complex, and multivesicular bodies, identifying probable sites of synthesis, modification, transport, and degradation.[15]

Genetics and regulation

The gene for DAT, known as DAT1, is located on chromosome 5p15.[2] The protein encoding region of the gene is over 64 kb long and comprises 15 coding segments or exons.[16] This gene has a variable number tandem repeat (VNTR) at the 3’ end (rs28363170) and another in the intron 8 region.[17] Differences in the VNTR have been shown to affect the basal level of expression of the transporter; consequently, researchers have looked for associations with dopamine-related disorders.[18]

Nurr1, a nuclear receptor that regulates many dopamine-related genes, can bind the promoter region of this gene and induce expression.[19] This promoter may also be the target of the transcription factor Sp-1.

While transcription factors control which cells express DAT, functional regulation of this protein is largely accomplished by kinases. MAPK,[20] CAMKII,[21] [22] PKA, and PKC[23] can modulate the rate at which the transporter moves dopamine or cause the internalization of DAT. Co-localized TAAR1 is an important regulator of the dopamine transporter that, when activated, phosphorylates DAT through protein kinase A (PKA) and protein kinase C (PKC) signaling.[24] [25] Phosphorylation by either protein kinase can result in DAT internalization (reuptake inhibition), but phosphorylation alone induces reverse transporter function (dopamine efflux).[26] Dopamine autoreceptors also regulate DAT by directly opposing the effect of TAAR1 activation.

The human dopamine transporter (hDAT) contains a high affinity extracellular zinc binding site which, upon zinc binding, inhibits dopamine reuptake and amplifies amphetamine-induced dopamine efflux in vitro.[27] [28] [29] In contrast, the human serotonin transporter (hSERT) and human norepinephrine transporter (hNET) do not contain zinc binding sites. Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of attention deficit hyperactivity disorder.[30]

Biological role and disorders

The rate at which DAT removes dopamine from the synapse can have a profound effect on the amount of dopamine in the cell. This is best evidenced by the severe cognitive deficits, motor abnormalities, and hyperactivity of mice with no dopamine transporters.[31] These characteristics have striking similarities to the symptoms of ADHD.

Differences in the functional VNTR have been identified as risk factors for bipolar disorder[32] and ADHD.[33] [34] Data has emerged that suggests there is also an association with stronger withdrawal symptoms from alcoholism, although this is a point of controversy.[35] [36] An allele of the DAT gene with normal protein levels is associated with non-smoking behavior and ease of quitting.[37] Additionally, male adolescents particularly those in high-risk families (ones marked by a disengaged mother and absence of maternal affection) who carry the 10-allele VNTR repeat show a statistically significant affinity for antisocial peers.[38] [39]

Increased activity of DAT is associated with several different disorders, including clinical depression.[40]

Mutations in DAT have been shown to cause dopamine transporter deficiency syndrome, an autosomal recessive movement disorder characterized by progressively worsening dystonia and parkinsonism.[41]

Pharmacology

The dopamine transporter is the target of substrates, dopamine releasers, transport inhibitors and allosteric modulators.[42] [43]

Cocaine blocks DAT by binding directly to the transporter and reducing the rate of transport.[8] In contrast, amphetamine enters the presynaptic neuron directly through the neuronal membrane or through DAT, competing for reuptake with dopamine. Once inside, it binds to or enters synaptic vesicles through . When amphetamine binds to TAAR1, it reduces the firing rate of the postsynaptic neuron and triggers protein kinase A and protein kinase C signaling, resulting in DAT phosphorylation. Phosphorylated DAT then either operates in reverse or withdraws into the presynaptic neuron and ceases transport. When amphetamine enters the synaptic vesicles through VMAT2, dopamine is released into the cytosol.[44] Amphetamine also produces dopamine efflux through a second TAAR1-independent mechanism involving CAMKIIα-mediated phosphorylation of the transporter, which putatively arises from the activation of DAT-coupled L-type calcium channels by amphetamine.

The dopaminergic mechanisms of each drug are believed to underlie the pleasurable feelings elicited by these substances.[3]

Interactions

Dopamine transporter has been shown to interact with:

Apart from these innate protein-protein interactions, recent studies demonstrated that viral proteins such as HIV-1 Tat protein interacts with the DAT[50] [51] and this binding may alter the dopamine homeostasis in HIV positive individuals which is a contributing factor for the HIV-associated neurocognitive disorders.[52]

Ligands and modulators

Substrates

Dopamine reuptake inhibitors (DRIs)

See main article: Dopamine reuptake inhibitor.

Typical or classical cocaine-like blockers

These agents may actually act as dopamine releasing agent-esque DAT negative allosteric modulators or "inverse agonists".[77]

Atypical non-psychostimulant blockers

These agents may actually act as simple competitive DAT blockers without releaser-like "inverse agonist" activity.

Unsorted blockers

Dopamine releasing agents (DRAs)

See main article: Dopamine releasing agent.

These agents are also known as substrate-type dopamine releasing agents and as DAT reversers.

Allosteric modulators

Positive allosteric modulators

Negative allosteric modulators

External links

Notes and References

  1. Carboni E, Tanda GL, Frau R, Di Chiara G . Blockade of the noradrenaline carrier increases extracellular dopamine concentrations in the prefrontal cortex: evidence that dopamine is taken up in vivo by noradrenergic terminals . Journal of Neurochemistry . 55 . 3 . 1067–70 . September 1990 . 2117046 . 10.1111/j.1471-4159.1990.tb04599.x . 23682303 .
  2. Vandenbergh DJ, Persico AM, Hawkins AL, Griffin CA, Li X, Jabs EW, Uhl GR . Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR . Genomics . 14 . 4 . 1104–6 . December 1992 . 1478653 . 10.1016/S0888-7543(05)80138-7 .
  3. Schultz W . Predictive reward signal of dopamine neurons . Journal of Neurophysiology . 80 . 1 . 1–27 . July 1998 . 9658025 . 10.1152/jn.1998.80.1.1 . 52857162 . free .
  4. Torres GE, Gainetdinov RR, Caron MG . Plasma membrane monoamine transporters: structure, regulation and function . Nature Reviews. Neuroscience . 4 . 1 . 13–25 . January 2003 . 12511858 . 10.1038/nrn1008 . 21545649 .
  5. Sonders MS, Zhu SJ, Zahniser NR, Kavanaugh MP, Amara SG . Multiple ionic conductances of the human dopamine transporter: the actions of dopamine and psychostimulants . The Journal of Neuroscience . 17 . 3 . 960–74 . February 1997 . 8994051 . 6573182 . 10.1523/JNEUROSCI.17-03-00960.1997 .
  6. Wheeler DD, Edwards AM, Chapman BM, Ondo JG . A model of the sodium dependence of dopamine uptake in rat striatal synaptosomes . Neurochemical Research . 18 . 8 . 927–36 . August 1993 . 8371835 . 10.1007/BF00998279 . 42196576 .
  7. Cameron KN, Solis E, Ruchala I, De Felice LJ, Eltit JM . Amphetamine activates calcium channels through dopamine transporter-mediated depolarization . Cell Calcium . 58 . 5 . 457–66 . November 2015 . 26162812 . 4631700 . 10.1016/j.ceca.2015.06.013 . One example of interest is CaMKII, which has been well characterized as an effector of Ca2+ currents downstream of L-type Ca2+ channels [21,22]. Interestingly, DAT is a CaMKII substrate and phosphorylated DAT favors the reverse transport of dopamine [48,49], constituting a possible mechanism by which electrical activity and L-type Ca2+ channels may modulate DAT states and dopamine release. ... In summary, our results suggest that pharmacologically, S(+)AMPH is more potent than DA at activating hDAT-mediated depolarizing currents, leading to L-type Ca2+ channel activation, and the S(+)AMPH-induced current is more tightly coupled than DA to open L-type Ca2+ channels. .
  8. Kilty JE, Lorang D, Amara SG . Cloning and expression of a cocaine-sensitive rat dopamine transporter . Science . 254 . 5031 . 578–9 . October 1991 . 1948035 . 10.1126/science.1948035 . 1991Sci...254..578K .
  9. Vaughan RA, Kuhar MJ . Dopamine transporter ligand binding domains. Structural and functional properties revealed by limited proteolysis . The Journal of Biological Chemistry . 271 . 35 . 21672–80 . August 1996 . 8702957 . 10.1074/jbc.271.35.21672 . free .
  10. Penmatsa A, Wang KH, Gouaux E . X-ray structure of dopamine transporter elucidates antidepressant mechanism . Nature . 503 . 7474 . 85–90 . November 2013 . 24037379 . 3904663 . 10.1038/nature12533 . 2013Natur.503...85P .
  11. Ciliax BJ, Drash GW, Staley JK, Haber S, Mobley CJ, Miller GW, Mufson EJ, Mash DC, Levey AI . Immunocytochemical localization of the dopamine transporter in human brain . The Journal of Comparative Neurology . 409 . 1 . 38–56 . June 1999 . 10363710 . 10.1002/(SICI)1096-9861(19990621)409:1<38::AID-CNE4>3.0.CO;2-1 . 46295607 .
  12. Liu Z, Yan SF, Walker JR, Zwingman TA, Jiang T, Li J, Zhou Y . Study of gene function based on spatial co-expression in a high-resolution mouse brain atlas . BMC Systems Biology . 1 . 19 . April 2007 . 17437647 . 1863433 . 10.1186/1752-0509-1-19 . free .
  13. Web site: Trace amine receptor: TA1 receptor. IUPHAR/BPS Guide to PHARMACOLOGY . International Union of Basic and Clinical Pharmacology . 22 September 2016 . Maguire JJ, Davenport AP . 19 July 2016 .
  14. Nirenberg MJ, Vaughan RA, Uhl GR, Kuhar MJ, Pickel VM . The dopamine transporter is localized to dendritic and axonal plasma membranes of nigrostriatal dopaminergic neurons . The Journal of Neuroscience . 16 . 2 . 436–47 . January 1996 . 8551328 . 6578661 . 10.1523/JNEUROSCI.16-02-00436.1996 .
  15. Hersch SM, Yi H, Heilman CJ, Edwards RH, Levey AI . Subcellular localization and molecular topology of the dopamine transporter in the striatum and substantia nigra . The Journal of Comparative Neurology . 388 . 2 . 211–27 . November 1997 . 9368838 . 10.1002/(SICI)1096-9861(19971117)388:2<211::AID-CNE3>3.0.CO;2-4 . 21202901 .
  16. Kawarai T, Kawakami H, Yamamura Y, Nakamura S . Structure and organization of the gene encoding human dopamine transporter . Gene . 195 . 1 . 11–8 . August 1997 . 9300814 . 10.1016/S0378-1119(97)00131-5 .
  17. Sano A, Kondoh K, Kakimoto Y, Kondo I . A 40-nucleotide repeat polymorphism in the human dopamine transporter gene . Human Genetics . 91 . 4 . 405–6 . May 1993 . 8500798 . 10.1007/BF00217369 . 39416578 .
  18. Miller GM, Madras BK . Polymorphisms in the 3'-untranslated region of human and monkey dopamine transporter genes affect reporter gene expression . Molecular Psychiatry . 7 . 1 . 44–55 . 2002 . 11803445 . 10.1038/sj/mp/4000921 . free .
  19. Sacchetti P, Mitchell TR, Granneman JG, Bannon MJ . Nurr1 enhances transcription of the human dopamine transporter gene through a novel mechanism . Journal of Neurochemistry . 76 . 5 . 1565–72 . March 2001 . 11238740 . 10.1046/j.1471-4159.2001.00181.x . 19410051 . free .
  20. Morón JA, Zakharova I, Ferrer JV, Merrill GA, Hope B, Lafer EM, Lin ZC, Wang JB, Javitch JA, Galli A, Shippenberg TS . Mitogen-activated protein kinase regulates dopamine transporter surface expression and dopamine transport capacity . The Journal of Neuroscience . 23 . 24 . 8480–8 . September 2003 . 13679416 . 6740378 . 10.1523/JNEUROSCI.23-24-08480.2003 .
  21. Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG . Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons . Neuron . 83 . 2 . 404–416 . July 2014 . 25033183 . 4159050 . 10.1016/j.neuron.2014.05.043 . AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012). .
  22. Vaughan RA, Foster JD . Mechanisms of dopamine transporter regulation in normal and disease states . Trends in Pharmacological Sciences . 34 . 9 . 489–96 . September 2013 . 23968642 . 3831354 . 10.1016/j.tips.2013.07.005 . AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72]. .
  23. Pristupa ZB, McConkey F, Liu F, Man HY, Lee FJ, Wang YT, Niznik HB . Protein kinase-mediated bidirectional trafficking and functional regulation of the human dopamine transporter . Synapse . 30 . 1 . 79–87 . September 1998 . 9704884 . 10.1002/(SICI)1098-2396(199809)30:1<79::AID-SYN10>3.0.CO;2-K . 20618165 .
  24. Miller GM . The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity . Journal of Neurochemistry . 116 . 2 . 164–76 . January 2011 . 21073468 . 3005101 . 10.1111/j.1471-4159.2010.07109.x .
  25. Lindemann L, Ebeling M, Kratochwil NA, Bunzow JR, Grandy DK, Hoener MC . Trace amine-associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors . Genomics . 85 . 3 . 372–85 . March 2005 . 15718104 . 10.1016/j.ygeno.2004.11.010 .
  26. Maguire JJ, Parker WA, Foord SM, Bonner TI, Neubig RR, Davenport AP . International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature . Pharmacological Reviews . 61 . 1 . 1–8 . March 2009 . 19325074 . 2830119 . 10.1124/pr.109.001107 .
  27. Krause J . SPECT and PET of the dopamine transporter in attention-deficit/hyperactivity disorder . Expert Review of Neurotherapeutics . 8 . 4 . 611–25 . April 2008 . 18416663 . 10.1586/14737175.8.4.611 . 24589993 . Zinc binds at ... extracellular sites of the DAT [103], serving as a DAT inhibitor. In this context, controlled double-blind studies in children are of interest, which showed positive effects of zinc [supplementation] on symptoms of ADHD [105,106]. It should be stated that at this time [supplementation] with zinc is not integrated in any ADHD treatment algorithm. .
  28. Sulzer D . How addictive drugs disrupt presynaptic dopamine neurotransmission . Neuron . 69 . 4 . 628–49 . February 2011 . 21338876 . 3065181 . 10.1016/j.neuron.2011.02.010 . They did not confirm the predicted straightforward relationship between uptake and release, but rather that some compounds including AMPH were better releasers than substrates for uptake. Zinc, moreover, stimulates efflux of intracellular [3H]DA despite its concomitant inhibition of uptake (Scholze et al., 2002). .
  29. Scholze P, Nørregaard L, Singer EA, Freissmuth M, Gether U, Sitte HH . The role of zinc ions in reverse transport mediated by monoamine transporters . The Journal of Biological Chemistry . 277 . 24 . 21505–13 . June 2002 . 11940571 . 10.1074/jbc.M112265200 . The human dopamine transporter (hDAT) contains an endogenous high affinity Zn2+ binding site with three coordinating residues on its extracellular face (His193, His375, and Glu396). ... Although Zn2+ inhibited uptake, Zn2+ facilitated [3H]MPP+ release induced by amphetamine, MPP+, or K+-induced depolarization specifically at hDAT but not at the human serotonin and the norepinephrine transporter (hNET). . free .
  30. Scassellati C, Bonvicini C, Faraone SV, Gennarelli M . Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses . Journal of the American Academy of Child and Adolescent Psychiatry . 51 . 10 . 1003–1019.e20 . October 2012 . 23021477 . 10.1016/j.jaac.2012.08.015 . With regard to zinc supplementation, a placebo controlled trial reported that doses up to 30 mg/day of zinc were safe for at least 8 weeks, but the clinical effect was equivocal except for the finding of a 37% reduction in amphetamine optimal dose with 30 mg per day of zinc.110 .
  31. Gainetdinov RR, Wetsel WC, Jones SR, Levin ED, Jaber M, Caron MG . 9629915 . Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity . Science . 283 . 5400 . 397–401 . January 1999 . 9888856 . 10.1126/science.283.5400.397 . 1999Sci...283..397G .
  32. Greenwood TA, Alexander M, Keck PE, McElroy S, Sadovnick AD, Remick RA, Kelsoe JR . Evidence for linkage disequilibrium between the dopamine transporter and bipolar disorder . American Journal of Medical Genetics . 105 . 2 . 145–51 . March 2001 . 11304827 . 10.1002/1096-8628(2001)9999:9999<::AID-AJMG1161>3.0.CO;2-8 .
  33. Yang B, Chan RC, Jing J, Li T, Sham P, Chen RY . A meta-analysis of association studies between the 10-repeat allele of a VNTR polymorphism in the 3'-UTR of dopamine transporter gene and attention deficit hyperactivity disorder . American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics . 144B . 4 . 541–50 . June 2007 . 17440978 . 10.1002/ajmg.b.30453 . 22881996 .
  34. Seymari A, Naseh A, Rezaei S, Salehi Z, Kousha M . The Relationship between Gene SLC6A3 Variable Number of Tandem Repeat (VNTR) and Attention-Deficit/Hyperactivity Disorder . Iranian Journal of Psychiatry . 19 . 1 . 99–106 . January 2024 . 38420272 . 10896761 . 10.18502/ijps.v19i1.14345 . free .
  35. Sander T, Harms H, Podschus J, Finckh U, Nickel B, Rolfs A, Rommelspacher H, Schmidt LG . Allelic association of a dopamine transporter gene polymorphism in alcohol dependence with withdrawal seizures or delirium . Biological Psychiatry . 41 . 3 . 299–304 . February 1997 . 9024952 . 10.1016/S0006-3223(96)00044-3 . 42947314 .
  36. Ueno S, Nakamura M, Mikami M, Kondoh K, Ishiguro H, Arinami T, Komiyama T, Mitsushio H, Sano A, Tanabe H . Identification of a novel polymorphism of the human dopamine transporter (DAT1) gene and the significant association with alcoholism . Molecular Psychiatry . 4 . 6 . 552–7 . November 1999 . 10578237 . 10.1038/sj.mp.4000562 . free .
  37. Ueno S . Genetic polymorphisms of serotonin and dopamine transporters in mental disorders . The Journal of Medical Investigation . 50 . 1–2 . 25–31 . February 2003 . 12630565 .
  38. Beaver KM, Wright JP, DeLisi M . Delinquent peer group formation: evidence of a gene x environment correlation . The Journal of Genetic Psychology . 169 . 3 . 227–44 . September 2008 . 18788325 . 10.3200/GNTP.169.3.227-244 . 46592146 .
  39. Web site: Florida State University . Specific Gene Found In Adolescent Men With Delinquent Peers . . 2 October 2008 . 8 October 2008 . Florida State University .
  40. Laasonen-Balk T, Kuikka J, Viinamäki H, Husso-Saastamoinen M, Lehtonen J, Tiihonen J . Striatal dopamine transporter density in major depression . Psychopharmacology . 144 . 3 . 282–5 . June 1999 . 10435396 . 10.1007/s002130051005 . 32882588 .
  41. Ng J, Zhen J, Meyer E, Erreger K, Li Y, Kakar N, Ahmad J, Thiele H, Kubisch C, Rider NL, Morton DH, Strauss KA, Puffenberger EG, D'Agnano D, Anikster Y, Carducci C, Hyland K, Rotstein M, Leuzzi V, Borck G, Reith ME, Kurian MA . Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood . Brain . 137 . Pt 4 . 1107–19 . April 2014 . 24613933 . 3959557 . 10.1093/brain/awu022 .
  42. Rothman RB, Ananthan S, Partilla JS, Saini SK, Moukha-Chafiq O, Pathak V, Baumann MH . Studies of the biogenic amine transporters 15. Identification of novel allosteric dopamine transporter ligands with nanomolar potency . The Journal of Pharmacology and Experimental Therapeutics . 353 . 3 . 529–38 . June 2015 . 25788711 . 4429677 . 10.1124/jpet.114.222299 .
  43. Aggarwal S, Liu X, Rice C, Menell P, Clark PJ, Paparoidamis N, Xiao YC, Salvino JM, Fontana AC, España RA, Kortagere S, Mortensen OV . Identification of a Novel Allosteric Modulator of the Human Dopamine Transporter . ACS Chem Neurosci . 10 . 8 . 3718–3730 . 2019 . 31184115 . 10.1021/acschemneuro.9b00262 . 6703927 .
  44. Eiden LE, Weihe E . VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse . Annals of the New York Academy of Sciences . 1216 . 1. 86–98 . January 2011 . 21272013 . 4183197 . 10.1111/j.1749-6632.2010.05906.x . 2011NYASA1216...86E .
  45. Wersinger C, Sidhu A . Attenuation of dopamine transporter activity by alpha-synuclein . Neuroscience Letters . 340 . 3 . 189–92 . April 2003 . 12672538 . 10.1016/S0304-3940(03)00097-1 . 54381509 .
  46. Lee FJ, Liu F, Pristupa ZB, Niznik HB . Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis . FASEB Journal . 15 . 6 . 916–26 . April 2001 . 11292651 . 10.1096/fj.00-0334com . free . 3406798 .
  47. Torres GE, Yao WD, Mohn AR, Quan H, Kim KM, Levey AI, Staudinger J, Caron MG . Functional interaction between monoamine plasma membrane transporters and the synaptic PDZ domain-containing protein PICK1 . Neuron . 30 . 1 . 121–34 . April 2001 . 11343649 . 10.1016/S0896-6273(01)00267-7 . 17318937 . free .
  48. Peck EG, Holleran KM, Curry AM, Holter KM, Estave PM, Sens JP, Locke JL, Ortelli OA, George BE, Dawes MH, West AM, Alexander NJ, Kiraly DD, Farris SP, Gould RW, McCool BA, Jones SR . Synaptogyrin-3 Prevents Cocaine Addiction and Dopamine Deficits . bioRxiv . August 2024 . 39211138 . 11361146 . 10.1101/2024.07.27.605436 .
  49. Carneiro AM, Ingram SL, Beaulieu JM, Sweeney A, Amara SG, Thomas SM, Caron MG, Torres GE . The multiple LIM domain-containing adaptor protein Hic-5 synaptically colocalizes and interacts with the dopamine transporter . The Journal of Neuroscience . 22 . 16 . 7045–54 . August 2002 . 12177201 . 6757888 . 10.1523/JNEUROSCI.22-16-07045.2002 .
  50. Midde NM, Yuan Y, Quizon PM, Sun WL, Huang X, Zhan CG, Zhu J . Mutations at tyrosine 88, lysine 92 and tyrosine 470 of human dopamine transporter result in an attenuation of HIV-1 Tat-induced inhibition of dopamine transport . Journal of Neuroimmune Pharmacology . 10 . 1 . 122–35 . March 2015 . 25604666 . 4388869 . 10.1007/s11481-015-9583-3 .
  51. Midde NM, Huang X, Gomez AM, Booze RM, Zhan CG, Zhu J . Mutation of tyrosine 470 of human dopamine transporter is critical for HIV-1 Tat-induced inhibition of dopamine transport and transporter conformational transitions . Journal of Neuroimmune Pharmacology . 8 . 4 . 975–87 . September 2013 . 23645138 . 3740080 . 10.1007/s11481-013-9464-6 .
  52. Purohit V, Rapaka R, Shurtleff D . Drugs of abuse, dopamine, and HIV-associated neurocognitive disorders/HIV-associated dementia . Molecular Neurobiology . 44 . 1 . 102–10 . August 2011 . 21717292 . 10.1007/s12035-011-8195-z . 13319355 .
  53. Hitri A, Hurd YL, Wyatt RJ, Deutsch SI . Molecular, functional and biochemical characteristics of the dopamine transporter: regional differences and clinical relevance . Clin Neuropharmacol . 17 . 1 . 1–22 . February 1994 . 8149355 . 10.1097/00002826-199402000-00001 .
  54. Harsing LG, Knoll J, Miklya I . Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum . Int J Mol Sci . 23 . 15 . August 2022 . 8543 . 35955676 . 9369307 . 10.3390/ijms23158543 . free .
  55. Book: Kostrzewa RM . Handbook of Neurotoxicity . Survey of Selective Monoaminergic Neurotoxins Targeting Dopaminergic, Noradrenergic, and Serotoninergic Neurons . Springer International Publishing . Cham . 2022 . 978-3-031-15079-1 . 10.1007/978-3-031-15080-7_53 . 159–198.
  56. Storch A, Ludolph AC, Schwarz J . Dopamine transporter: involvement in selective dopaminergic neurotoxicity and degeneration . J Neural Transm (Vienna) . 111 . 10–11 . 1267–1286 . October 2004 . 15480838 . 10.1007/s00702-004-0203-2 .
  57. Sotnikova TD, Beaulieu JM, Gainetdinov RR, Caron MG . Molecular biology, pharmacology and functional role of the plasma membrane dopamine transporter . CNS Neurol Disord Drug Targets . 5 . 1 . 45–56 . February 2006 . 16613553 . 10.2174/187152706784111579 .
  58. Aceto MD, Botton I, Martin R, Levitt M, Bentley HC, Speight PT . Pharmacologic properties and mechanism of action of amfonelic acid . Eur J Pharmacol . 10 . 3 . 344–354 . 1970 . 4393073 . 10.1016/0014-2999(70)90206-2 .
  59. Porrino LJ, Goodman NL, Sharpe LG . Intravenous self-administration of the indirect dopaminergic agonist amfonelic acid by rats . Pharmacol Biochem Behav . 31 . 3 . 623–626 . November 1988 . 2908003 . 10.1016/0091-3057(88)90240-7 .
  60. Garattini S . Pharmacology of amineptine, an antidepressant agent acting on the dopaminergic system: a review . Int Clin Psychopharmacol . 12 . Suppl 3 . S15–S19 . July 1997 . 9347388 . 10.1097/00004850-199707003-00003 .
  61. Bonnet JJ, Chagraoui A, Protais P, Costentin J . Interactions of amineptine with the neuronal dopamine uptake system: neurochemical in vitro and in vivo studies . J Neural Transm . 69 . 3–4 . 211–220 . 1987 . 3625193 . 10.1007/BF01244342 .
  62. Evans EA, Sullivan MA . Abuse and misuse of antidepressants . Subst Abuse Rehabil . 5 . 107–120 . 2014 . 25187753 . 4140701 . 10.2147/SAR.S37917 . free .
  63. Haddad P . Do antidepressants have any potential to cause addiction? . J Psychopharmacol . 13 . 3 . 300–307 . 1999 . 10512092 . 10.1177/026988119901300321 .
  64. Dutta AK, Zhang S, Kolhatkar R, Reith ME . Dopamine transporter as target for drug development of cocaine dependence medications . Eur J Pharmacol . 479 . 1–3 . 93–106 . October 2003 . 14612141 . 10.1016/j.ejphar.2003.08.060 .
  65. Pergolizzi J, Breve F, Magnusson P, LeQuang JA, Varrassi G . Cocaethylene: When Cocaine and Alcohol Are Taken Together . Cureus . 14 . 2 . e22498 . February 2022 . 35345678 . 8956485 . 10.7759/cureus.22498 . free .
  66. Landry MJ . An overview of cocaethylene, an alcohol-derived, psychoactive, cocaine metabolite . J Psychoactive Drugs . 24 . 3 . 273–276 . 1992 . 1432406 . 10.1080/02791072.1992.10471648 .
  67. Book: Aggarwal S, Mortensen OV . Drug Development in Psychiatry . 30 . 101–129 . 2023 . 36928847 . 10074400 . 10.1007/978-3-031-21054-9_4 . Discovery and Development of Monoamine Transporter Ligands . 978-3-031-21053-2 . Advances in Neurobiology .
  68. Newman AH, Ku T, Jordan CJ, Bonifazi A, Xi ZX . New Drugs, Old Targets: Tweaking the Dopamine System to Treat Psychostimulant Use Disorders . Annu Rev Pharmacol Toxicol . 61 . 609–628 . January 2021 . 33411583 . 9341034 . 10.1146/annurev-pharmtox-030220-124205 .
  69. Glennon RA, Young R . Neurobiology of 3,4-methylenedioxypyrovalerone (MDPV) and α-pyrrolidinovalerophenone (α-PVP) . Brain Res Bull . 126 . Pt 1 . 111–126 . September 2016 . 27142261 . 5817884 . 10.1016/j.brainresbull.2016.04.011 .
  70. Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW . Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products . Neuropsychopharmacology . 38 . 4 . 552–562 . March 2013 . 23072836 . 3572453 . 10.1038/npp.2012.204 .
  71. Cheng MH, Block E, Hu F, Cobanoglu MC, Sorkin A, Bahar I . Insights into the Modulation of Dopamine Transporter Function by Amphetamine, Orphenadrine, and Cocaine Binding . Front Neurol . 6 . 134 . 2015 . 26106364 . 4460958 . 10.3389/fneur.2015.00134 . free .
  72. Katz JL, Newman AH, Izenwasser S . Relations between heterogeneity of dopamine transporter binding and function and the behavioral pharmacology of cocaine . Pharmacol Biochem Behav . 57 . 3 . 505–512 . July 1997 . 9218275 . 10.1016/s0091-3057(96)00441-8 .
  73. Bergman J, France CP, Holtzman SG, Katz JL, Koek W, Stephens DN . Agonist efficacy, drug dependence, and medications development: preclinical evaluation of opioid, dopaminergic, and GABAA-ergic ligands . Psychopharmacology (Berl) . 153 . 1 . 67–84 . December 2000 . 11255930 . 10.1007/s002130000567 .
  74. Izenwasser S, Newman AH, Cox BM, Katz JL . The cocaine-like behavioral effects of meperidine are mediated by activity at the dopamine transporter . Eur J Pharmacol . 297 . 1–2 . 9–17 . February 1996 . 8851160 . 10.1016/0014-2999(95)00696-6 .
  75. Book: White MW, Archer JR . Novel Psychoactive Substances . Pipradrol and Pipradrol Derivatives . Elsevier . 2013 . 978-0-12-415816-0 . 10.1016/b978-0-12-415816-0.00010-9 . 233–259.
  76. Golovko AI, Bonitenko EY, Ivanov MB, Barinov VA, Zatsepin EP . The neurochemical bases of the pharmacological activity of ligands of monoamine-transport systems . Neurochemical Journal . 10 . 3 . 2016 . 1819-7124 . 10.1134/S1819712416030065 . 173–183.
  77. Heal DJ, Gosden J, Smith SL . Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine . Neuropharmacology . 87 . 19–40 . December 2014 . 24953830 . 10.1016/j.neuropharm.2014.06.012 .
  78. Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL . Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter . Drug Alcohol Depend . 147 . 1–19 . February 2015 . 25548026 . 4297708 . 10.1016/j.drugalcdep.2014.12.005 .
  79. Book: Hauck Newman A, Katz JL . Transporters as Targets for Drugs . Atypical Dopamine Uptake Inhibitors that Provide Clues About Cocaine's Mechanism at the Dopamine Transporter . Topics in Medicinal Chemistry . Springer Berlin Heidelberg . Berlin, Heidelberg . 4 . 2008 . 978-3-540-87911-4 . 10.1007/7355_2008_027 . 95–129.
  80. Naglich AC, Brown ES, Adinoff B . Systematic review of preclinical, clinical, and post-marketing evidence of bupropion misuse potential . Am J Drug Alcohol Abuse . 45 . 4 . 341–354 . 2019 . 30601027 . 10.1080/00952990.2018.1545023 .
  81. Noe G, Shah K, Ongchuan S, Munjal S . Clinical Presentations of Bupropion Prescription Drug Misuse: A Systematic Review . J Clin Psychopharmacol . 44 . 3 . 284–290 . 2024 . 38656298 . 10.1097/JCP.0000000000001858 .
  82. Aikoye S, Basiru TO, Nwoye I, Adereti I, Asuquo S, Ezeokoli A, Hardy J, Umudi O . A Systematic Review of Abuse or Overprescription of Bupropion in American Prisons and a Synthesis of Case Reports on Bupropion Abuse in American Prison and Non-prison Systems . Cureus . 15 . 3 . e36189 . March 2023 . 37065297 . 10104426 . 10.7759/cureus.36189 . free .
  83. Costa R, Oliveira NG, Dinis-Oliveira RJ . Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects . Drug Metab Rev . 51 . 3 . 293–313 . August 2019 . 31124380 . 10.1080/03602532.2019.1620763 .
  84. Jordan CJ, Cao J, Newman AH, Xi ZX . Progress in agonist therapy for substance use disorders: Lessons learned from methadone and buprenorphine . Neuropharmacology . 158 . 107609 . November 2019 . 31009632 . 6745247 . 10.1016/j.neuropharm.2019.04.015 .
  85. Salamone JD, Correa M . The Neurobiology of Activational Aspects of Motivation: Exertion of Effort, Effort-Based Decision Making, and the Role of Dopamine . Annu Rev Psychol . 75 . 1–32 . January 2024 . 37788571 . 10.1146/annurev-psych-020223-012208 . 10234/207207 . free .
  86. Hersey M, Bartole MK, Jones CS, Newman AH, Tanda G . Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors . Molecules . 28 . 13 . July 2023 . 5270 . 37446929 . 10343811 . 10.3390/molecules28135270 . free .
  87. Kouhnavardi S, Ecevitoglu A, Dragačević V, Sanna F, Arias-Sandoval E, Kalaba P, Kirchhofer M, Lubec J, Niello M, Holy M, Zehl M, Pillwein M, Wackerlig J, Murau R, Mohrmann A, Beard KR, Sitte HH, Urban E, Sagheddu C, Pistis M, Plasenzotti R, Salamone JD, Langer T, Lubec G, Monje FJ . A Novel and Selective Dopamine Transporter Inhibitor, (S)-MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions . Biomolecules . 12 . 7 . June 2022 . 881 . 35883437 . 9312958 . 10.3390/biom12070881 . free .
  88. Hersey M, Bacon AK, Bailey LG, Coggiano MA, Newman AH, Leggio L, Tanda G . Psychostimulant Use Disorder, an Unmet Therapeutic Goal: Can Modafinil Narrow the Gap? . Front Neurosci . 15 . 656475 . 2021 . 34121988 . 8187604 . 10.3389/fnins.2021.656475 . free .
  89. Book: Hersey M, Tanda G . Pharmacological Advances in Central Nervous System Stimulants . Modafinil, an atypical CNS stimulant? . Adv Pharmacol . 99 . 287–326 . 2024 . 38467484 . 10.1016/bs.apha.2023.10.006 . 978-0-443-21933-7 .
  90. Book: Rothman RB . Erinoff L, Brown RM . A Review of the Effects of Dopaminergic Agents in Humans: Implications for Medication Development . Neurobiological Models for Evaluating Mechanisms Underlying Cocaine Addiction (NIDA Research Monograph 145) . U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute on Drug Abuse . 1994 . 4 August 2024 . 67–87.
  91. Rothman RB, Glowa JR . A review of the effects of dopaminergic agents on humans, animals, and drug-seeking behavior, and its implications for medication development. Focus on GBR 12909 . Mol Neurobiol . 11 . 1–3 . 1–19 . 1995 . 8561954 . 10.1007/BF02740680 .
  92. Böning J, Fuchs G . Nomifensine and psychological dependence--a case report . Pharmacopsychiatry . 19 . 5 . 386–388 . September 1986 . 3774872 . 10.1055/s-2007-1017275 .
  93. Veinberg G, Vavers E, Orlova N, Kuznecovs J, Domracheva I, Vorona M, Zvejniece L, Dambrova M . Stereochemistry of phenylpiracetam and its methyl derivative: improvement of the pharmacological profile . Chemistry of Heterocyclic Compounds . 51 . 7 . 2015 . 0009-3122 . 10.1007/s10593-015-1747-9 . 601–606 . Phenylpiracetam was originally designed as a nootropic drug for the sustenance and improvement of the physical condition and cognition abilities of Soviet space crews.2 Later, especially during the last decade, phenylpiracetam was introduced into general clinical practice in Russia and in some Eastern European countries. The possible target receptors and mechanisms for the acute activity of this drug remained unclear, until very recently it was found that (R)-phenylpiracetam (5) (MRZ-9547) is a selective dopamine transporter inhibitor that moderately stimulates striatal dopamine release.19.
  94. Zvejniece L, Svalbe B, Vavers E, Makrecka-Kuka M, Makarova E, Liepins V, Kalvinsh I, Liepinsh E, Dambrova M . S-phenylpiracetam, a selective DAT inhibitor, reduces body weight gain without influencing locomotor activity . Pharmacology, Biochemistry, and Behavior . 160 . 21–29 . September 2017 . 28743458 . 10.1016/j.pbb.2017.07.009 . 13658335 .
  95. Stutz PV, Golani LK, Witkin JM . Animal models of fatigue in major depressive disorder . Physiology & Behavior . 199 . 300–305 . February 2019 . 30513290 . 10.1016/j.physbeh.2018.11.042 . In a study performed by Sommer et al. (2014), healthy rats treated with the selective dopamine transport (DAT) inhibitor MRZ-9547 (Fig. 1) chose high effort, high reward more often than their untreated matched controls. Unlike similar studies, however, depressive symptoms were not induced before treatment; rather, baseline healthy controls were compared to healthy rats treated with MRZ-9547. [...] In one study, the selective DAT inhibitor MRZ-9547 increased the number of lever presses more than untreated controls (Sommer et al., 2014). The investigators concluded that such effort-based “decision making in rodents could provide an animal model for motivational dysfunctions related to effort expenditure such as fatigue, e.g. in Parkinson's disease or major depression.” Based upon the findings with MRZ-9547, they suggested that this drug mechanism might be a valuable therapeutic entity for fatigue in neurological and neuropsychiatric disorders. [...] A high effort bias been reported with bupropion (Randall et al., 2015), lisdexamfetamine (Yohn etal., 2016e), and the DA uptake blockers MRZ-9547 (Sommer et al., 2014), PRX-14040 (Fig. 1) (Yohn et al., 2016d) and GBR12909 (Fig. 1) (Yohn et al., 2016c). .
  96. Sommer S, Danysz W, Russ H, Valastro B, Flik G, Hauber W . The dopamine reuptake inhibitor MRZ-9547 increases progressive ratio responding in rats . The International Journal of Neuropsychopharmacology . 17 . 12 . 2045–2056 . December 2014 . 24964269 . 10.1017/S1461145714000996 . Here, we tested the effects of MRZ-9547 [...], and its l-enantiomer MRZ-9546 on effort-related decision making in rats. The racemic form of these compounds referred to as phenotropil has been shown to stimulate motor activity in rats (Zvejniece et al., 2011) and enhance physical capacity and cognition in humans (Malykh and Sadaie, 2010). [...] MRZ-9547 turned out to be a DAT inhibitor as shown by displacement of binding of [125I] RTI-55 (IC50 = 4.82 ± 0.05 μM, n=3) to human recombinant DAT expressed in CHO-K1 cells and inhibition of DA uptake (IC50 = 14.5 ± 1.6 μM, n=2) in functional assays in the same cells. It inhibited norepinephrine transporter (NET) with an IC50 of 182 μM (one experiment in duplicate). The potencies for the l-enantiomer MRZ-9546 were as follows: DAT binding (Ki = 34.8 ± 14.8 μM, n=3), DAT function (IC50 = 65.5 ± 8.3 μM, n=2) and NET function (IC50 = 667 μM, one experiment performed in duplicate). .
  97. Dekundy A, Mela F, Hofmann M, Danysz W . Effects of dopamine uptake inhibitor MRZ-9547 in animal models of Parkinson's disease . Journal of Neural Transmission . 122 . 6 . 809–818 . June 2015 . 25319446 . 10.1007/s00702-014-1326-8 .
  98. Tanda G, Hersey M, Hempel B, Xi ZX, Newman AH . Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder . Curr Opin Pharmacol . 56 . 13–21 . February 2021 . 32927246 . 8247144 . 10.1016/j.coph.2020.07.007 .
  99. Ngo Q, Plante DT . An Update on the Misuse and Abuse Potential of Pharmacological Treatments for Central Disorders of Hypersomnolence . Current Sleep Medicine Reports . 8 . 4 . 19 September 2022 . 2198-6401 . 10.1007/s40675-022-00227-4 . 147–159.
  100. Yang J, Gao J . Solriamfetol for the treatment of excessive daytime sleepiness associated with narcolepsy . Expert Rev Clin Pharmacol . 12 . 8 . 723–728 . August 2019 . 31215815 . 10.1080/17512433.2019.1632705 .
  101. Mikelman SR, Guptaroy B, Schmitt KC, Jones KT, Zhen J, Reith ME, Gnegy ME . Tamoxifen Directly Interacts with the Dopamine Transporter . J Pharmacol Exp Ther . 367 . 1 . 119–128 . October 2018 . 30108161 . 7250473 . 10.1124/jpet.118.248179 .
  102. Salamone JD, Correa M, Ferrigno S, Yang JH, Rotolo RA, Presby RE . The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation . Pharmacol Rev . 70 . 4 . 747–762 . October 2018 . 30209181 . 6169368 . 10.1124/pr.117.015107 .
  103. Desibhatla M . The Development and Evaluation of Novel DA Transport Inhibitors and their Effects on Effort-Related Motivation: A Review . Honors Scholar Theses . 16 June 2021 . 10 August 2024.
  104. Yohn SE, Gogoj A, Haque A, Lopez-Cruz L, Haley A, Huxley P, Baskin P, Correa M, Salamone JD . Evaluation of the effort-related motivational effects of the novel dopamine uptake inhibitor PRX-14040 . Pharmacol Biochem Behav . 148 . 84–91 . September 2016 . 27296079 . 10.1016/j.pbb.2016.06.004 .
  105. Pinterova N, Horsley RR, Palenicek T . Synthetic Aminoindanes: A Summary of Existing Knowledge . Front Psychiatry . 8 . 236 . 2017 . 29204127 . 5698283 . 10.3389/fpsyt.2017.00236 . free .
  106. Simmler LD, Rickli A, Schramm Y, Hoener MC, Liechti ME . Pharmacological profiles of aminoindanes, piperazines, and pipradrol derivatives . Biochem Pharmacol . 88 . 2 . 237–244 . March 2014 . 24486525 . 10.1016/j.bcp.2014.01.024 .
  107. Blough BE, Landavazo A, Partilla JS, Decker AM, Page KM, Baumann MH, Rothman RB . Alpha-ethyltryptamines as dual dopamine-serotonin releasers . Bioorganic & Medicinal Chemistry Letters . 24 . 19 . 4754–4758 . October 2014 . 25193229 . 4211607 . 10.1016/j.bmcl.2014.07.062 .
  108. Banks ML, Bauer CT, Blough BE . Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys . Exp Clin Psychopharmacol . 22 . 3 . 274–284 . June 2014 . 24796848 . 10.1037/a0036595 . etal . 4067459.
  109. Glennon RA, Dukat MG . α-Ethyltryptamine: A Ratiocinatory Review of a Forgotten Antidepressant . ACS Pharmacology & Translational Science . 6 . 12 . 1780–1789 . December 2023 . 38093842 . 10.1021/acsptsci.3c00139 . 10714429 .
  110. Oeri HE . Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy . Journal of Psychopharmacology . 35 . 5 . 512–536 . May 2021 . 32909493 . 8155739 . 10.1177/0269881120920420 .
  111. Blough BE, Landavazo A, Partilla JS, Decker AM, Page KM, Baumann MH, Rothman RB . Alpha-ethyltryptamines as dual dopamine-serotonin releasers . Bioorganic & Medicinal Chemistry Letters . 24 . 19 . 4754–4758 . October 2014 . 25193229 . 4211607 . 10.1016/j.bmcl.2014.07.062 .
  112. Rothman RB, Baumann MH . Monoamine transporters and psychostimulant drugs . Eur J Pharmacol . 479 . 1–3 . 23–40 . October 2003 . 14612135 . 10.1016/j.ejphar.2003.08.054 .
  113. Rothman RB, Baumann MH . Therapeutic potential of monoamine transporter substrates . Curr Top Med Chem . 6 . 17 . 1845–1859 . 2006 . 17017961 . 10.2174/156802606778249766 .
  114. Rothman RB, Baumann MH . Targeted screening for biogenic amine transporters: potential applications for natural products . Life Sci . 78 . 5 . 512–518 . December 2005 . 16202429 . 10.1016/j.lfs.2005.09.001 .
  115. Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, Birkes J, Young R, Glennon RA . In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates . J Pharmacol Exp Ther . 307 . 1 . 138–145 . October 2003 . 12954796 . 10.1124/jpet.103.053975 .
  116. Hutson PH, Pennick M, Secker R . Preclinical pharmacokinetics, pharmacology and toxicology of lisdexamfetamine: a novel d-amphetamine pro-drug . Neuropharmacology . 87 . 41–50 . December 2014 . 24594478 . 10.1016/j.neuropharm.2014.02.014 .
  117. Heal DJ, Cheetham SC, Smith SL . The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety . Neuropharmacology . 57 . 7–8 . 608–618 . December 2009 . 19761781 . 10.1016/j.neuropharm.2009.08.020 .
  118. Green AR, King MV, Shortall SE, Fone KC . The preclinical pharmacology of mephedrone; not just MDMA by another name . Br J Pharmacol . 171 . 9 . 2251–2268 . May 2014 . 24654568 . 3997268 . 10.1111/bph.12628 .
  119. Simmons SJ, Leyrer-Jackson JM, Oliver CF, Hicks C, Muschamp JW, Rawls SM, Olive MF . DARK Classics in Chemical Neuroscience: Cathinone-Derived Psychostimulants . ACS Chem Neurosci . 9 . 10 . 2379–2394 . October 2018 . 29714473 . 6197900 . 10.1021/acschemneuro.8b00147 .
  120. Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV . The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue . Neuropsychopharmacology . 37 . 5 . 1192–1203 . April 2012 . 22169943 . 3306880 . 10.1038/npp.2011.304 .
  121. Rothman RB, Blough BE, Baumann MH . Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions . AAPS J . 9 . 1 . E1–10 . January 2007 . 17408232 . 2751297 . 10.1208/aapsj0901001 .
  122. Parker EM, Cubeddu LX . Comparative effects of amphetamine, phenylethylamine and related drugs on dopamine efflux, dopamine uptake and mazindol binding . J Pharmacol Exp Ther . 245 . 1 . 199–210 . April 1988 . 3129549 .
  123. Patrick KS, Markowitz JS . Pharmacology of methylphenidate, amphetamine enantiomers and pemoline in attention-deficit hyperactivity disorder . Human Psychopharmacology: Clinical and Experimental . November 1997 . 12 . 6 . 527–546 . 0885-6222 . 1099-1077 . 10.1002/(SICI)1099-1077(199711/12)12:6<527::AID-HUP932>3.0.CO;2-U . 144548631 .
  124. Nishino S, Mignot E . Pharmacological aspects of human and canine narcolepsy . Prog Neurobiol . 52 . 1 . 27–78 . May 1997 . 9185233 . 10.1016/s0301-0082(96)00070-6 . 31839355 . free .
  125. Fuller RW, Perry KW, Bymaster FP, Wong DT . Comparative effects of pemoline, amfonelic acid and amphetamine on dopamine uptake and release in vitro and on brain 3,4-dihydroxyphenylacetic acid concentration in spiperone-treated rats . The Journal of Pharmacy and Pharmacology . 30 . 3 . 197–198 . March 1978 . 24701 . 10.1111/j.2042-7158.1978.tb13201.x .
  126. Blough BE, Landavazo A, Decker AM, Partilla JS, Baumann MH, Rothman RB . Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes . Psychopharmacology . 231 . 21 . 4135–4144 . October 2014 . 24800892 . 4194234 . 10.1007/s00213-014-3557-7 .
  127. Zhao G, Qin GW, Wang J, Chu WJ, Guo LH . Functional activation of monoamine transporters by luteolin and apigenin isolated from the fruit of Perilla frutescens (L.) Britt . Neurochem Int . 56 . 1 . 168–176 . January 2010 . 19815045 . 10.1016/j.neuint.2009.09.015 .
  128. Zhang J, Liu X, Lei X, Wang L, Guo L, Zhao G, Lin G . Discovery and synthesis of novel luteolin derivatives as DAT agonists . Bioorg Med Chem . 18 . 22 . 7842–7848 . November 2010 . 20971650 . 10.1016/j.bmc.2010.09.049 .
  129. Schmitt KC, Rothman RB, Reith ME . Nonclassical pharmacology of the dopamine transporter: atypical inhibitors, allosteric modulators, and partial substrates . J Pharmacol Exp Ther . 346 . 1 . 2–10 . July 2013 . 23568856 . 3684841 . 10.1124/jpet.111.191056 .
  130. Rothman RB, Dersch CM, Carroll FI, Ananthan S . Studies of the biogenic amine transporters. VIII: identification of a novel partial inhibitor of dopamine uptake and dopamine transporter binding . Synapse . 43 . 4 . 268–274 . March 2002 . 11835522 . 10.1002/syn.10046 .
  131. Pariser JJ, Partilla JS, Dersch CM, Ananthan S, Rothman RB . Studies of the biogenic amine transporters. 12. Identification of novel partial inhibitors of amphetamine-induced dopamine release . J Pharmacol Exp Ther . 326 . 1 . 286–295 . July 2008 . 18441249 . 2562894 . 10.1124/jpet.108.139675 .
  132. Rothman RB, Dersch CM, Ananthan S, Partilla JS . Studies of the biogenic amine transporters. 13. Identification of "agonist" and "antagonist" allosteric modulators of amphetamine-induced dopamine release . J Pharmacol Exp Ther . 329 . 2 . 718–728 . May 2009 . 19244097 . 2672863 . 10.1124/jpet.108.149088 .
  133. Book: Macolino-Kane CM, Ciallella JR, Lipinski CA, Reaume AG . Drug Repositioning . Phenotypic Screening . CRC Press . Boca Raton . Frontiers in Neurotherapeutics . 14 July 2017 . 978-1-315-37366-9 . 10.4324/9781315373669-7 . 121–145 .
  134. Al'tshuler RA . Comparative Molecular Model Estimation of the Affinity of Phenylethylamines to the Binding Sites of Membrane Transporters . Pharmaceutical Chemistry Journal . 39 . 4 . 2005 . 0091-150X . 10.1007/s11094-005-0110-3 . 169–175.
  135. Bulling S, Schicker K, Zhang YW, Steinkellner T, Stockner T, Gruber CW, Boehm S, Freissmuth M, Rudnick G, Sitte HH, Sandtner W . The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters . J Biol Chem . 287 . 22 . 18524–18534 . May 2012 . 22451652 . 3365767 . 10.1074/jbc.M112.343681 . free .
  136. Harsing LG, Sershen H, Lajtha A . Evidence that ibogaine releases dopamine from the cytoplasmic pool in isolated mouse striatum . J Neural Transm Gen Sect . 96 . 3 . 215–225 . 1994 . 7826572 . 10.1007/BF01294788 .
  137. Wells GB, Lopez MC, Tanaka JC . The effects of ibogaine on dopamine and serotonin transport in rat brain synaptosomes . Brain Res Bull . 48 . 6 . 641–647 . April 1999 . 10386845 . 10.1016/s0361-9230(99)00053-2 . free .
  138. Nepal B, Das S, Reith ME, Kortagere S . Overview of the structure and function of the dopamine transporter and its protein interactions . Front Physiol . 14 . 1150355 . 2023 . 36935752 . 10020207 . 10.3389/fphys.2023.1150355 . free .
  139. Aggarwal S, Liu X, Rice C, Menell P, Clark PJ, Paparoidamis N, Xiao YC, Salvino JM, Fontana AC, España RA, Kortagere S, Mortensen OV . Identification of a Novel Allosteric Modulator of the Human Dopamine Transporter . ACS Chem Neurosci . 10 . 8 . 3718–3730 . August 2019 . 31184115 . 6703927 . 10.1021/acschemneuro.9b00262 .
  140. Nguyen H, Cheng MH, Lee JY, Aggarwal S, Mortensen OV, Bahar I . Allosteric modulation of serotonin and dopamine transporters: New insights from computations and experiments . Curr Res Physiol . 7 . 100125 . 2024 . 38836245 . 11148570 . 10.1016/j.crphys.2024.100125 .
  141. Aggarwal S, Cheng MH, Salvino JM, Bahar I, Mortensen OV . Functional Characterization of the Dopaminergic Psychostimulant Sydnocarb as an Allosteric Modulator of the Human Dopamine Transporter . Biomedicines . 9 . 6 . June 2021 . 634 . 34199621 . 8227285 . 10.3390/biomedicines9060634 . free .
  142. Tosh DK, Janowsky A, Eshleman AJ, Warnick E, Gao ZG, Chen Z, Gizewski E, Auchampach JA, Salvemini D, Jacobson KA . Scaffold Repurposing of Nucleosides (Adenosine Receptor Agonists): Enhanced Activity at the Human Dopamine and Norepinephrine Sodium Symporters . J Med Chem . 60 . 7 . 3109–3123 . April 2017 . 28319392 . 5501184 . 10.1021/acs.jmedchem.7b00141 .
  143. Srivastava DK, Navratna V, Tosh DK, Chinn A, Sk MF, Tajkhorshid E, Jacobson KA, Gouaux E . Structure of the human dopamine transporter and mechanisms of inhibition . Nature . 632 . 8025 . 672–677 . August 2024 . 39112705 . 11324517 . 10.1038/s41586-024-07739-9 . 2024Natur.632..672S .
  144. Rothman RB, Ananthan S, Partilla JS, Saini SK, Moukha-Chafiq O, Pathak V, Baumann MH . Studies of the biogenic amine transporters 15. Identification of novel allosteric dopamine transporter ligands with nanomolar potency . J Pharmacol Exp Ther . 353 . 3 . 529–538 . June 2015 . 25788711 . 4429677 . 10.1124/jpet.114.222299 .
  145. Moerke MJ, Ananthan S, Banks ML, Eltit JM, Freitas KC, Johnson AR, Saini SK, Steele TW, Negus SS . Interactions between Cocaine and the Putative Allosteric Dopamine Transporter Ligand SRI-31142 . J Pharmacol Exp Ther . 367 . 2 . 222–233 . November 2018 . 30150482 . 6170971 . 10.1124/jpet.118.250902 .

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