Advertisement

Neuropharmacology of Synthetic Cathinones

  • Michael H. BaumannEmail author
  • Hailey M. Walters
  • Marco Niello
  • Harald H. Sitte
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 252)

Abstract

Synthetic cathinones are derivatives of the naturally occurring compound cathinone, the main psychoactive ingredient in the khat plant Catha edulis. Cathinone is the β-keto analog of amphetamine, and all synthetic cathinones display a β-keto moiety in their structure. Several synthetic cathinones are widely prescribed medications (e.g., bupropion, Wellbutrin®), while others are problematic drugs of abuse (e.g., 4-methylmethcathinone, mephedrone). Similar to amphetamines, synthetic cathinones are psychomotor stimulants that exert their effects by impairing the normal function of plasma membrane transporters for dopamine (DAT), norepinephrine (NET), and 5-HT (SERT). Ring-substituted cathinones like mephedrone are transporter substrates that evoke neurotransmitter release by reversing the normal direction of transporter flux (i.e., releasers), whereas pyrrolidine-containing cathinones like 3,4-methylenedioxypyrovalerone (MDPV) are potent transporter inhibitors that block neurotransmitter uptake (i.e., blockers). Regardless of molecular mechanism, all synthetic cathinones increase extracellular monoamine concentrations in the brain, thereby enhancing cell-to-cell monoamine signaling. Here, we briefly review the mechanisms of action, structure-activity relationships, and in vivo pharmacology of synthetic cathinones. Overall, the findings show that certain synthetic cathinones are powerful drugs of abuse that could pose significant risk to users.

Keywords

Cathinone Dopamine Monoamine Serotonin Stimulant Transporter 

Acronyms of the Discussed New Psychoactive Substances (NPS)

4-Bromo MCAT

1-(4-Bromophenyl)-2-(methylamino)propan-1-one (brephedrone)

4-Chloro MCAT

1-(4-Chlorophenyl)-2-(methylamino)propan-1-one (clephedrone)

4-Fluoro MCAT

1-(4-Fluorophenyl)-2-(methylamino)propan-1-one (flephedrone)

4-Methyl MCAT (4-MMC)

2-(Methylamino)-1-(4-methylphenyl)propan-1-one (mephedrone)

4-Methoxy MCAT

1-(4-Methoxyphenyl)-2-(methylamino)propan-1-one (methedrone)

4-TFM MCAT

2-(Methylamino)-1-[4-(trifluoromethyl)phenyl]propan-1-one

MCAT

2-(Methylamino)-1-phenylpropan-1-one (methcathinone)

MDMA

1-(2H-1,3-Benzodioxol-5-yl)-N-methylpropan-2-amine

MDMC

1-(2H-1,3-Benzodioxol-5-yl)-2-(methylamino)propan-1-one (methylone)

MDPV

1-(2H-1,3-Benzodioxol-5-yl)-2-(pyrrolidin-1-yl)pentan-1-one

α-PBP

1-Phenyl-2-(pyrrolidin-1-yl)butan-1-one

α-PHP

1-Phenyl-2-(pyrrolidin-1-yl)hexan-1-one

α-PPP

1-Phenyl-2-(pyrrolidin-1-yl)propan-1-one

α-PVP

1-Phenyl-2-(pyrrolidin-1-yl)pentan-1-one

Notes

Acknowledgments

The research program of Dr. Baumann is generously supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, grant DA00523.

References

  1. Aarde SM, Huang PK, Creehan KM, Dickerson TJ, Taffe MA (2013a) The novel recreational drug 3,4-methylenedioxypyrovalerone (MDPV) is a potent psychomotor stimulant: self-administration and locomotor activity in rats. Neuropharmacology 71:130–140PubMedPubMedCentralGoogle Scholar
  2. Aarde SM, Angrish D, Barlow DJ, Wright MJ Jr, Vandewater SA, Creehan KM et al (2013b) Mephedrone (4-methylmethcathinone) supports intravenous self-administration in Sprague-Dawley and Wistar rats. Addict Biol 18(5):786–799PubMedPubMedCentralGoogle Scholar
  3. Aarde SM, Creehan KM, Vandewater SA, Dickerson TJ, Taffe MA (2015) In vivo potency and efficacy of the novel cathinone α-pyrrolidinopentiophenone and 3,4-methylenedioxypyrovalerone: self-administration and locomotor stimulation in male rats. Psychopharmacology (Berl) 232(16):3045–3055PubMedCentralGoogle Scholar
  4. Adams SV, DeFelice LJ (2003) Ionic currents in the human serotonin transporter reveal inconsistencies in the alternating access hypothesis. Biophys J 85(3):1548–1559PubMedPubMedCentralGoogle Scholar
  5. Al-Hebshi NN, Skaugh N (2005) Khat (Catha edulis)- an updated review. Addict Biol 10(4):299–307PubMedGoogle Scholar
  6. Alexander SP, Kelly E, Marrion NV, Peters JA, Faccenda E, Harding SD (2017) The concise guide to pharmacology 2017/18: transporters. Br J Pharmacol 174(Suppl 1):S360–S446PubMedPubMedCentralGoogle Scholar
  7. Arbuthnott GW, Fairbrother IS, Butcher SP (1990) Dopamine release and metabolism in the rat striatum: an analysis by ‘in vivo’ brain microdialysis. Pharmacol Ther 48(3):281–293PubMedGoogle Scholar
  8. Axelrod J, Whitby LG, Hertting G (1961) Effect of psychotropic drugs on the uptake of H3-norepinephrine by tissues. Science 133(3450):383–384PubMedGoogle Scholar
  9. Banks ML, Worst TJ, Rusyniak DE, Sprague JE (2014) Synthetic cathinones (“bath salts”). J Emerg Med 46(5):632–642PubMedPubMedCentralGoogle Scholar
  10. Bauer CT, Banks ML, Blough BE, Negus SS (2013) Use of intracranial self-stimulation to evaluate abuse-related and abuse-limiting effects of monoamine releasers in rats. Br J Pharmacol 168(4):850–862PubMedPubMedCentralGoogle Scholar
  11. Baumann MH, Wang X, Rothman RB (2007) 3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings. Psychopharmacology (Berl) 189(4):407–424Google Scholar
  12. Baumann MH, Clark RD, Rothman RB (2008) Locomotor stimulation produced by 3,4-methylenedioxymethamphetamine (MDMA) is correlated with dialysate levels of serotonin and dopamine in rat brain. Pharmacol Biochem Behav 90(2):208–217PubMedPubMedCentralGoogle Scholar
  13. Baumann MH, Clark RD, Woolverton WL, Wee S, Blough BE, Rothman RB (2011) In vivo effects of amphetamine analogs reveal evidence for serotonergic inhibition of mesolimbic dopamine transmission in the rat. J Pharmacol Exp Ther 337(1):218–225PubMedPubMedCentralGoogle Scholar
  14. Baumann MH, Ayestas MA Jr, Partilla JS, Sink JR, Shulgin AT, Daley PF et al (2012) The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue. Neuropsychopharmacology 37(5):1192–1203PubMedGoogle Scholar
  15. Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M (2013) Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive “bath salts” products. Neuropsychopharmacology 38(4):552–562PubMedGoogle Scholar
  16. Baumann MH (2014) Awash in a sea of ‘bath salts’: implications for biomedical research and public health. Addiction 109(10):157–159Google Scholar
  17. Baumann MH, Solis E Jr, Watterson LR, Marusich JA, Fantegrossi WE, Wiley JL (2014a) Bath salts, spice, and related designer drugs: the science behind the headlines. J Neurosci 34(46):15150–15158PubMedPubMedCentralGoogle Scholar
  18. Baumann MH, Bulling S, Benaderet TS, Saha K, Avestas MA, Partilla JS et al (2014b) Evidence for a role of transporter-mediated currents in the depletion of brain serotonin induced by serotonin transporter substrates. Neuropsychopharmacology 39(6):1355–1365PubMedPubMedCentralGoogle Scholar
  19. Beveridge TJ, Smith HR, Daunais JB, Nader MA, Porrino LJ (2006) Chronic cocaine self-administration is associated with altered functional activity in the temporal lobes of non human primates. Eur J Neurosci 23(11):3109–3118PubMedGoogle Scholar
  20. Bonano JS, Glennon RA, De Felice LJ, Banks ML, Negus SS (2014) Abuse-related and abuse-limiting effects of methcathinone and the synthetic “bath salts” cathinone analogs methylenedioxypyrovalerone (MDPV), methylone and mephedrone on intracranial self-stimulation in rats. Psychopharmacology (Berl) 231(1):199–207Google Scholar
  21. Bonano JS, Banks ML, Kolanos R, Sakloth F, Barnier ML, Glennon RA et al (2015) Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues. Br J Pharmacol 172(10):2433–2444PubMedPubMedCentralGoogle Scholar
  22. Bönisch H (1986) The role of co-transported sodium in the effect of indirectly acting sympathomimetic amines. Naunyn Schmiedebergs Arch Pharmacol 332(2):135–141PubMedGoogle Scholar
  23. 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(2):346–355PubMedGoogle Scholar
  24. Callaway CW, Kuczenski R, Segal DS (1989) Reserpine enhances amphetamine stereotypies without increasing amphetamine-induced changes in striatal dialysate dopamine. Brain Res 505(1):83–90PubMedGoogle Scholar
  25. Cameron KN, Kolanos R, Solis E Jr, Glennon RA, Da Felice LF (2013) Bath salts components mephedrone and methylenedioxypyrovalerone (MDPV) act synergistically at the human dopamine transporter. Br J Pharmacol 168(7):1750–1757PubMedPubMedCentralGoogle Scholar
  26. Centers for Disease Control and Prevention (CDC) (2011) Emergency department visits after use of a drug sold as “bath salts” – Michigan, November 13, 2010-March 31, 2011. MMWR Morb Mort Wkly Rep 60(19):624–627Google Scholar
  27. Cercato C, Roizenblatt VA, Leança CC, Segal A, Lopes Filho AP, Mancini MC et al (2009) A randomized double-blind placebo-controlled study of the long-term efficacy and safety of diethylpropion in the treatment of obese subjects. Int J Obes (Lond) 33(8):857–865Google Scholar
  28. Chen NH, Reith ME (1994) Effects of locally applied cocaine, lidocaine, and various uptake blockers on monoamine transmission in the ventral tegmental area of freely moving rats: a microdialysis study on monoamine interrelationships. J Neurochem 63(5):1701–1713PubMedGoogle Scholar
  29. Cozzi NV, Sievert MK, Shulgin AT, Jacob P 3rd, Ruoho AE (1999) Inhibition of plasma membrane monoamine transporters by beta-ketoamphetamines. Eur J Pharmacol 281(1):63–69Google Scholar
  30. Cozzi NV, Brandt SD, Daley PF, Partilla JS, Rothman RB, Tulzer A et al (2013) Pharmacological examination of trifluoromethyl ring-substituted methcathinone analogs. Eur J Pharmacol 699(1–3):180–187PubMedGoogle Scholar
  31. Creehan KM, Vandewater SA, RAffe MA (2015) Intravenous self-administration of mephedrone, methylone and MDMA in female rats. Neuropharmacology 92:90–97PubMedPubMedCentralGoogle Scholar
  32. De Felice LJ, Glennon RA, Negus SS (2014) Synthetic cathinones: chemical phylogeny, physiology, and neuropharmacology. Life Sci 97(1):20–26PubMedGoogle Scholar
  33. Degenhardt L, Baxter AJ, Lee YY, Hall W, Sara GE, Johns N et al (2014) The global epidemiology and burden of psychostimulant dependence: findings from the Global Burden of Disease Study 2010. Drug Alcohol Depend 137:36–47PubMedGoogle Scholar
  34. Deroche-Gamonet V, Belin D, Piazza PV (2004) Evidence for addiction-like behavior in the rat. Science 305(5686):1014–1017PubMedGoogle Scholar
  35. Devroye C, Filip M, Przegalinski E, McCreary AC, Spampinato U (2013) Serotonin2C receptors and drug addiction: focus on cocaine. Exp Brain Res 230(4):537–545PubMedGoogle Scholar
  36. Dhillon S, Yang LP, Curran MP (2008) Bupropion: a review of its use in the management of major depressive disorder. Drugs 68(5):653–689PubMedGoogle Scholar
  37. Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 85(14):5274–5278PubMedPubMedCentralGoogle Scholar
  38. Drug Enforcement Administration (DEA), Department of Justice (2013) Establishment of drug codes for 26 substances. Final rule. Fed Regist 78(3):664–666Google Scholar
  39. Dwoskin LP, Rauhut AS, King-Paspisil KA, Bardo MT (2006) Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent. CNS Drug Rev 12(3–4):178–207PubMedGoogle Scholar
  40. Elmore JS, Dillon-Carter O, Partilla JS, Ellefsen KN, Concheiro M, Suzuki M et al (2017) Pharmacokinetic profiles and pharmacodynamic effects for methylone and its metabolites in rats. Neuropsychopharmacology 42(3):649–660PubMedGoogle Scholar
  41. Emerson TS, Cisek JE (1993) Methcathinone: a Russian designer amphetamine infiltrates the rural midwest. Ann Emerg Med 22(12):1897–1903PubMedGoogle Scholar
  42. Engidawork E (2017) Pharmacological and toxicological effects of Catha edulis F. (Khat). Phytother Res 31(7):1019–1028PubMedGoogle Scholar
  43. Eshleman AJ, Henningsen RA, Neve KA, Janowsky A (1994) Release of dopamine via the human transporter. Mol Pharmacol 45(2):312–316PubMedGoogle Scholar
  44. Eshleman AJ, Wolfrum KM, Hatfield MG, Johnson RA, Murphy KV, Janowsky A (2013) Substituted methcathinones differ in transporter and receptor interactions. Biochem Pharmacol 85(12):1803–1815PubMedPubMedCentralGoogle Scholar
  45. Eshleman AJ, Wolfrum KM, Reed JF, Kim SO, Swanson T, Johnson RA (2017) Structure-activity relationships of substituted cathinones, with transporter binding, uptake, and release. J Pharmacol Exp Ther 360(1):33–47PubMedPubMedCentralGoogle Scholar
  46. Espana RA, Jones SR (2013) Presynaptic dopamine modulation by stimulant self-administration. Front Biosci (Schol Ed) 5:261–276Google Scholar
  47. Fantegrossi WE, Gannon BM, Zimmerman SM, Rice KC (2013) In vivo effects of abused ‘bath salt’ constituent 3,4-methylenedioxypyrovalerone (MDPV) in mice: drug discrimination, thermoregulation, and locomotor activity. Neuropsychopharmacology 38(4):563–573PubMedGoogle Scholar
  48. Faraone SV (2018) The pharmacology of amphetamine and methylphenidate: relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neurosci Biobehav Rev 87:255–270PubMedGoogle Scholar
  49. Farre M, Abanades S, Roset PN, Peiro AM, Torrens M, O’Mathuna B et al (2007) Pharmacological interaction between 3,4-methylenedioxymethamphetamine (ecstasy) and paroxetine: pharmacological effects and pharmacokinetics. J Pharmacol Exp Ther 323(3):954–962PubMedGoogle Scholar
  50. Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR (2007) New insights into the mechanism of action of amphetamines. Annu Rev Pharmacol Toxicol 47:681–698PubMedGoogle Scholar
  51. Florin SM, Kuczenski R, Segal DS (1995) Effects of reserpine on extracellular caudate dopamine and hippocampus norepinephrine responses to amphetamine and cocaine: mechanistic and behavioral considerations. J Pharmacol Exp Ther 274(1):231–241PubMedGoogle Scholar
  52. Gannon BM, Williamson A, Suzuki M, Rice KC, Fantegrossi WE (2016) Stereoselective effects of abused “bath salt” constituent 3,4-methylenedioxypyrovalerone in mice: drug discrimination, locomotor activity, and thermoregulation. J Pharmacol Exp Ther 356(3):615–623PubMedPubMedCentralGoogle Scholar
  53. Gannon BM, Rice KC, Collins GT (2017) Reinforcing effects of abused ‘bath salts’ constituents 3,4-methylenedioxypyrovalerone and α-pyrrolidinopentiophenone and their enantiomers. Behav Pharmacol 28(7):578–581PubMedPubMedCentralGoogle Scholar
  54. Gannon BM, Galindo KI, Mesmin MP, Sulima A, Rice KC, Collins GT (2018) Relative reinforcing effects of second-generation synthetic cathinones: acquisition of self-administration and fixed-ratio dose-response curves in rats. Neuropharmacology 134(Pt A):28–35PubMedGoogle Scholar
  55. Gatch MB, Taylor CM, Forster MJ (2013) Locomotor stimulant and discriminative stimulus effects of ‘bath salt’ cathinones. Behav Pharmacol 24(5–6):437–447PubMedPubMedCentralGoogle Scholar
  56. Giros B, el Mestikawy S, Bertrand L, Caron MG (1991) Cloning and functional characterization of a cocaine-sensitive dopamine transporter. FEBS Lett 295(1–3):149–154PubMedGoogle Scholar
  57. Glennon RA, Yousif M, Naiman N, Kalix P (1987) Methcathinone: a new and potent amphetamine-like agent. Pharmacol Biochem Behav 26(3):547–551PubMedGoogle Scholar
  58. Glennon RA, Dukat M (2017) Structure-activity relationships of synthetic cathinones. Curr Top Behav Neurosci 32:19–47PubMedPubMedCentralGoogle Scholar
  59. Goldberg J, Gardos G, Cole JO (1973) A controlled evaluation of pyrovalerone in chronically fatigued volunteers. Int Pharmacopsychiatry 8(1):60–69PubMedGoogle Scholar
  60. Goldstone MS (1993) ‘Cat’: methcathinone – a new drug of abuse. JAMA 269(19):2508PubMedGoogle Scholar
  61. Grohol J (2017) Top 25 psychiatric medications for 2016. https://psychcentral.com/blog/top-25-psychiatric-medications-for-2016. Accessed 8 Sep 2018
  62. Gundlah C, Martin KF, Heal DJ, Auerback SB (1997) In vivo criteria to differentiate monoamine reuptake inhibitors from releasing agents: sibutramine is a reuptake inhibitor. J Pharmacol Exp Ther 283(2):581–591PubMedGoogle Scholar
  63. Hadlock GV, Webb KM, McFadden LM, Chu PW, Ellis JD, Allen SC et al (2011) 4-Methylmethcathinone (mephedrone): neuropharmacological effects of a designed stimulant of abuse. J Pharmacol Exp Ther 339(2):530–536PubMedPubMedCentralGoogle Scholar
  64. Heikkila RE, Orlansky H, Cogen G (1975) Studies on the distinction between uptake inhibition and release of (3H)dopamine in rat brain tissue slices. Biochem Pharmacol 24(8):847–852PubMedGoogle Scholar
  65. Henningfield JE, Cohen C, Heishman SJ (1991) Drug self-administration methods in abuse liability evaluation. Br J Addict 86(12):1571–1577PubMedGoogle Scholar
  66. Héron C, Costentin J, Bonnet JJ (1994) Evidence that pure uptake inhibitors including cocaine interact slowly with the dopamine neuronal carrier. Eur J Pharmacol 264(3):391–398PubMedGoogle Scholar
  67. Hilber B, Scholze P, Dorostkar MM, Sandtner W, Holy M, Boehm S et al (2005) Serotonin-transporter mediated effux: a pharmacological analysis of amphetamines and non-amphetamines. Neuropharmacology 49(6):811–819PubMedGoogle Scholar
  68. Howell LL, Kimmel HL (2008) Monoamine transporters and psychostimulant addiction. Biochem Pharmacol 75(1):196–217PubMedGoogle Scholar
  69. Howell LL, Cunningham KA (2015) Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder. Pharmacol Rev 67(1):176–197PubMedPubMedCentralGoogle Scholar
  70. Huang PK, Aarde SM, Angrish D, Houseknecht KL, Dickerson TJ, Taffe MA (2012) Contrasting effects of d-methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxypyrovalerone, and 4-methylmethcathinone on wheel activity in rats. Drug Alcohol Depend 126(1–2):168–175PubMedPubMedCentralGoogle Scholar
  71. Huestis MA, Brandt SD, Rana S, Auwärter V, Baumann MH (2017) Impact of novel psychoactive substances on clinical and forensic toxicology and global public health. Clin Chem 63(10):1564–1569PubMedGoogle Scholar
  72. Huskinson SL, Naylor JE, Townsend EA, Rowlett JK, Blough BE, Freeman KB (2017) Self-administration and behavioral economics of second-generation synthetic cathinones in male rats. Psychopharmacology (Berl) 234(4):589–598Google Scholar
  73. Hysek CM, Simmler LD, Nicola VG, Vischer N, Donzelli M, Krahenbuhl S et al (2012) Duloxetine inhibits effects of MDMA (“ecstasy”) in vitro and in humans in a randomized placebo-controlled laboratory study. PLoS One 7(5):e36476PubMedPubMedCentralGoogle Scholar
  74. Ikemoto S, Bonci A (2014) Neurocircuitry of drug reward. Neuropharmacology 76(Pt B):329–341PubMedGoogle Scholar
  75. Iverson L (2006) Neurotransmitter transporters and their impact on the development of psychopharmacology. Br J Pharmacol 147(Suppl 1):S82–S88Google Scholar
  76. Jardetzky O (1966) Simple allosteric model for membrane pumps. Nature 211(5052):969–970PubMedPubMedCentralGoogle Scholar
  77. Johnson AR, Banks ML, Selley DE, Negus SS (2018) Amphetamine maintenance differentially modulates effects of cocaine, methylenedioxypyrovalerone (MDPV), and methamphetamine on intracranial self-stimulation and nucleus accumbens dopamine in rats. Neuropsychopharmacology 43(8):1753–1762PubMedGoogle Scholar
  78. Kaizaki A, Tanaka S, Numazawa S (2014) New recreational drug 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (alpha-PVP) activates central nervous system via dopaminergic neuron. J Toxicol Sci 39(1):1–6PubMedGoogle Scholar
  79. Kalix P (1980) Hypermotility of the amphetamine type induced by a constituent of khat leaves. Br J Pharmacol 68(1):11–13PubMedPubMedCentralGoogle Scholar
  80. Kalix P, Glennon RA (1986) Further evidence for an amphetamine-like mechanism of action of the alkaloid cathinone. Biochem Pharmacol 35(18):3015–3019PubMedGoogle Scholar
  81. Kalix P (1990) Pharmacological properties of the stimulant khat. Pharmacol Ther 48(3):397–416PubMedGoogle Scholar
  82. Kaminski BJ, Griffiths RR (1994) Intravenous self-injection of methcathinone in the baboon. Pharmacol Biochem Behav 27(4):981–983Google Scholar
  83. Kaminska K, Noworyta-Sokolowska K, Górska A, Rzemieniec J, Wnuk A, Wojtas A et al (2018) The effects of exposure to mephedrone during adolescence on brain neurotransmission and neurotoxicity in adult rats. Neurotox Res 34(3):525–537PubMedPubMedCentralGoogle Scholar
  84. Karch SB (2015) Cathinone neurotoxicity (“The 3Ms”). Curr Neuropharmacol 13(1):21–25PubMedPubMedCentralGoogle Scholar
  85. Kehr J, Ichinose F, Yoshitake S, Goiny M, Sievertsson T, Nyberg F et al (2011) Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats. Br J Pharmacol 164(8):1949–1958PubMedPubMedCentralGoogle Scholar
  86. Kilty JE, Lorang D, Amara SG (1991) Cloning and expression of a cocaine-sensitive rat dopamine transporter. Science 254(5031):578–579PubMedGoogle Scholar
  87. Kolanos R, Solis E Jr, Sakloth F, De Felice LJ, Glennon RA (2013) “Deconstruction” of the abused synthetic cathinone methylenedioxypyrovalerone (MDPV) and an examination of effects at the human dopamine transporter. ACS Chem Nerosci 4(12):1524–1529Google Scholar
  88. Kolanos R, Sakloth F, Jain AD, Partilla JS, Baumann MH, Glennon RA (2015a) Structural modification of the designer stimulant α-pyrrolidinovalerophenone (α-PVP) influences potency at dopamine transporters. ACS Chem Nerosci 6(10):1726–1731Google Scholar
  89. Kolanos R, Partilla JS, Baumann MH, Hutsell BA, Banks ML, Negus SS et al (2015b) Stereoselective actions of methylenedioxypyrovalerone (MDPV) to inhibit dopamine and norepinephrine transporters and facilitate intracranial self-stimulation in rats. ACS Chem Nerosci 6(5):771–777Google Scholar
  90. Kristensen AS, Andersen J, Jørgensen TN, Sørensen L, Erikson J, Loland CJ et al (2011) SLC6 neurotransmitter transporters: structure, function and regulation. Pharmacol Rev 63(3):585–640PubMedGoogle Scholar
  91. Liang NY, Rutledge CO (1982) Evidence for carrier-mediated efflux of dopamine from corpus striatum. Biochem Pharmacol 31(15):2479–2484PubMedGoogle Scholar
  92. Liechti ME, Vollenweider FX (2001) Which neuroreceptors mediate the subjective effects of MDMA in humans? A summary of mechanistic studies. Hum Psychopharmacol 16(8):589–598PubMedGoogle Scholar
  93. López-Arnau R, Martinez-Clemente J, Pubill D, Escubedo E, Camarasa J (2012) Comparative neuropharmacology of three psychostimulant cathinone derivatives: butylone, mephedrone and methylone. Br J Pharmacol 167(2):407–420PubMedPubMedCentralGoogle Scholar
  94. Madras BK (2017) The growing problem of new psychoactive substances (NPS). Curr Top Behav Neurosci 32:1–18PubMedGoogle Scholar
  95. Mager S, Min C, Henry DJ, Chavkin C, Hoffman BJ, Davidson N (1994) Conducting states of a mammalian serotonin transporter. Neuron 12(4):845–859PubMedGoogle Scholar
  96. Marusich JA, Grant KR, Blough BE, Wiley JL (2012) Effects of synthetic cathinones contained in “bath salts” on motor behavior and a functional observational battery in mice. Neurotoxicology 33(5):1305–1313PubMedPubMedCentralGoogle Scholar
  97. Marusich JA, Antonazzo KR, Wiley JL, Blough BE, Partilla JS, Baumann MH (2014) Pharmacology of novel synthetic stimulants structurally related to the “bath salts” constituent 3,4-methylenedioxypyrovalerone (MDPV). Neuropharmacology 87:206–213PubMedPubMedCentralGoogle Scholar
  98. Mayer FP, Wimmer L, Dillon-Carter O, Partilla JS, Burchardt NV, Mihovilovic MD (2016) Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters. Br J Pharmacol 173(17):2657–2668PubMedPubMedCentralGoogle Scholar
  99. Mehta NB (1974) Meta chloro substituted-α-butylamino-propiophenones. Burroughs Wellcome Company. North Carolina, USA. US3819706Google Scholar
  100. Meltzer PC, Butler D, Deschamps JR, Madras BK (2006) 1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (pyrovalerone) analogues: a promising class of monoamine uptake inhibitors. J Med Chem 49(4):1420–1432PubMedPubMedCentralGoogle Scholar
  101. Mollenhauer HH, Morré DJ, Rowe LD (1990) Alteration of intracellular traffic by monensin; mechanism, specificity and relationship to toxicity. Biochim Biophys Acta 1031(2):225–246PubMedGoogle Scholar
  102. Motbey CP, Clemens KJ, Apetz N, Winstock AR, Ramsey J, Li KM et al (2013) High levels of intravenous mephedrone (4-methylmethcathinone) self-administration in rats: neural consequences and comparison with methamphetamine. J Psychopharmacol 27(9):823–836PubMedGoogle Scholar
  103. Nagai F, Nonaka R, Satoh Hisashi Kamimura K (2007) The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain. Eur J Pharmacol 559(2–3):132–137PubMedGoogle Scholar
  104. Negus SS, Miller LL (2014) Intracranial self-stimulation to evaluate abuse potential of drugs. Pharmacol Rev 66(3):869–917PubMedPubMedCentralGoogle Scholar
  105. Negus SS, Banks ML (2017) Decoding the structure of abuse potential for new psychoactive substances: structure-activity relationships for abuse-related effects of 4-substituted methcathinone analogs. Curr Top Behav Neurosci 32:119–131PubMedPubMedCentralGoogle Scholar
  106. Nomikos GG, Damsma G, Wenkstern D, Fibiger HC (1990) In vivo characterization of locally applied dopamine uptake inhibitors by striatal microdialysis. Synapse 6(1):106–112PubMedGoogle Scholar
  107. Pacholczyk T, Blakely RD, Amara SG (1991) Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature 350(6316):350–354Google Scholar
  108. 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(2):368–373PubMedGoogle Scholar
  109. Pifl C, Reither H, Hornykiewicz O (2015) The profile of mephedrone on human monoamine transporters differs from 3,4-methylenedioxymethamphetamine primarily by lower potency at the vesicular monoamine transporter. Eur J Pharmacol 755:119–126PubMedGoogle Scholar
  110. Prosser JM, Nelson LS (2012) The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol 8(1):33–42PubMedGoogle Scholar
  111. Quick MW (2003) Regulating the conducting states of a mammalian serotonin transporter. Neuron 40(3):537–549PubMedGoogle Scholar
  112. Raiteri M, Cerrito F, Cervoni AM, Del Carmine R, Ribera MT, Levi G (1978) Release of dopamine from striatal synaptosomes. Ann Ist Super Sanita 14(1):97–110PubMedGoogle Scholar
  113. Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH et al (2015) Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter. Drug Alcohol Depend 147:1–19PubMedGoogle Scholar
  114. Rickli A, Hoener MD, Liechti ME (2015) Monoamine transporter and receptor interaction profiles of novel psychoactive substances: para-halogenated amphetamines and pyrovalerone cathinones. Eur Neuropsychopharmacol 25(3):365–376PubMedGoogle Scholar
  115. Robertson SD, Matthies HJ, Galli A (2009) A closer look at amphetamine-induced reverse transport and trafficking of the dopamine and norepinephrine transporters. Mol Neurobiol 39(2):73–80PubMedPubMedCentralGoogle Scholar
  116. Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI et al (2001) Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 39(1):32–41PubMedGoogle Scholar
  117. Rothman RB, Baumann MH (2003) Monoamine transporters and psychostimulant drugs. Eur J Pharmacol 479(1–3):23–40PubMedGoogle Scholar
  118. Rothman RB, Clark RD, Partilla JS, Baumann MH (2003a) (+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters. J Pharmacol Exp Ther 305(3):1191–1199PubMedGoogle Scholar
  119. Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA et al (2003b) 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):138–145PubMedGoogle Scholar
  120. Rothman RB, Blough BE, Woolverton WL, Anderson KG, Negus SS, Mello NK et al (2005) Development of a rationally designed, low abuse potential, biogenic amine releaser that suppresses cocaine self-administration. J Pharmacol Exp Ther 313(3):1361–1369PubMedGoogle Scholar
  121. Rudnick G (1998) Bioenergetics of neurotransmitter transport. J Bioenerg Biomembr 30(2):173–185PubMedGoogle Scholar
  122. Saha K, Partilla JS, Lehner KR, Seddik A, Stockner T, Holy M et al (2015) “Second-generation” mephedrone analogs, 4-MEC and 4-MePPP, differentially affect monoamine transporter function. Neuropsychopharmacology 40(6):1321–1331PubMedPubMedCentralGoogle Scholar
  123. Sakloth F, Kolanos R, Mosier PD, Bonano JS, Banks ML, Partilla JS et al (2015) Steric parameters, molecular modeling and hydropathic interaction analysis of the pharmacology of para-substituted methcathinone analogues. Br J Pharmacol 172(9):2210–2218PubMedPubMedCentralGoogle Scholar
  124. Sanchez C, Reines EH, Montgomery SA (2014) A comparative review of escitalopram, paroxetine, and sertraline: are they all alike? Int Clin Psychopharmacol 29(4):185–196PubMedPubMedCentralGoogle Scholar
  125. Sandtner W, Stockner T, Hasenhuetl PS, Partilla JS, Seddik A, Zhang YW et al (2016) Binding mode selection determines the action of ecstasy homologs at monoamine transporters. Mol Pharmacol 89(1):165–175PubMedPubMedCentralGoogle Scholar
  126. Schicker K, Uzelac Z, Gesmonde J, Bulling S, Stockner T, Freissmuth M (2012) Unifying concept of serotonin transporter-associated currents. J Biol Chem 287(2):438–445PubMedGoogle Scholar
  127. Schindler CW, Thorndike EB, Goldberg SR, Lehner KR, Cozzi NV, Brandt SD et al (2016) Reinforcing and neurochemical effects of the “bath salts” constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats. Pyschopharmacology (Berl) 233(10):1981–1990Google Scholar
  128. Scholze P, Zwach J, Kattinger A, Pifl C, Singer EA, Sitte HH (2000) Transporter-mediated release: a superfusion study on human embryonic kidney cells stably expressing the human serotonin transporter. J Pharmacol Exp Ther 293(3):870–878PubMedGoogle Scholar
  129. Schütte J (1961) Anorexigenic propiophenones. Temmler Werke, Hamburg-Neugraben, Germany. US3001910AGoogle Scholar
  130. Seddik A, Geerke DP, Stockner T, Holy M, Kudlacek O, Cozzi NV et al (2017) Combined simulation and mutation studies to elucidate selectivity of unsubstituted amphetamine-like cathinones at the dopamine transporter. Mol Inform 36(5–6)Google Scholar
  131. Seeger E (1967) α-Pyrrolidino ketones. Boehringer Ingelheim GmbH, Biberach an der Riss, Germany. Boehringer Ingelheim G.m.b.H. US3314970Google Scholar
  132. Shanks KG, Dann T, Behonick G, Terrell A (2012) Analysis of first and second-generation legal highs for synthetic cannabinoids and synthetic stimulants by ultra-performance liquid chromatography and time of flight mass spectrometry. J Anal Toxicol 36(6):360–371PubMedGoogle Scholar
  133. Shekar A, Aguilar JI, Galli G, Cozzi NV, Brandt SD, Ruoho AE et al (2017) Atypical dopamine efflux caused by 3,4-methylenedioxypyrovalerone (MDPV) via the human dopamine transporter. J Chem Neuroanat 83-84:69–74PubMedPubMedCentralGoogle Scholar
  134. Shimada S, Kitayam S, Lin CL, Patel A, Nanthakumar E, Gregor P et al (1991) Cloning and expression of a cocaine-sensitive dopamine transporter complementary DNA. Science 254(5031):576–578PubMedGoogle Scholar
  135. Shortall SE, Macerola AE, Swaby RT, Jayson R, Korsah C, Pillidge KE et al (2013) Behavioural and neurochemical comparison of chronic intermittent cathinone, mephedrone and MDMA administration to the rat. Eur Neuropsychopharmacol 23(9):1085–1095PubMedGoogle Scholar
  136. Shortall SE, Spicer CH, Ebling FJ, Green AR, Fone KC, King MV (2016) Contribution of serotonin and dopamine to changes in core body temperature and locomotor activity in rats following repeated administration of mephedrone. Addict Biol 21(6):1127–1139PubMedGoogle Scholar
  137. Sikk K, Taba P (2015) Methcathinone “kitchen chemistry” and permanent neurological damage. Int Rev Neurobiol 120:257–271PubMedGoogle Scholar
  138. Simmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J et al (2013) Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol 168(2):458–470PubMedGoogle Scholar
  139. 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(3):1289–1297PubMedGoogle Scholar
  140. Sitte HH, Scholze P, Schloss P, Pifl C, Singer EA (2000) Characterization of carrier-mediated efflux in human embryonic kidney 293 cells stably expressing the rat serotonin transporter: a superfusion study. J Neurochem 73(3):1317–1324Google Scholar
  141. Sitte HH, Freissmuth M (2015) Amphetamines, new psychoactive drugs and the monoamine transporter cycle. Trends Pharmacol Sci 36(1):41–50PubMedGoogle Scholar
  142. Solis E Jr (2017) Electrophysiological actions of synthetic cathinones on monoamine transporters. Curr Top Behav Neurosci 32:73–92PubMedPubMedCentralGoogle Scholar
  143. Sonders MS, Amara SG (1996) Channels in transporters. Curr Opin Neurobiol 6(3):294–302PubMedGoogle Scholar
  144. Sonders MS, Zhu SJ, Zahniser NR, Kavanaugh MP, Amara SG (1997) Multiple ionic conductances of the human dopamine transporter: actions of dopamine and psychostimulants. J Neurosci 17(3):960–974PubMedGoogle Scholar
  145. Spiller HA, Ryan ML, Weston RG, Jansen J (2011) Clinical experience with and analytical confirmation of “bath salts” and “legal highs” (synthetic cathinones) in the United States. Clin Toxical (Phila) 49(6):499–505Google Scholar
  146. Stepens A, Logina I, Liguts V, Aldins P, Eksteina I, Platkajis A et al (2008) A Parkinsonian syndrome in methcathinone users and the role of manganese. N Engl J Med 358(10):1009–1017PubMedGoogle Scholar
  147. Suplicy H, Boguszewski CL, dos Santos CM, do Desterro de Figueiredo M, Cuha DR, Radominski R (2014) A comparative study of five centrally acting drugs on the pharmacological treatment of obesity. Int J Obes (Lond) 38(8):1097–1103Google Scholar
  148. Suyama JA, Sakloth F, Kolanos R, Glennon RA, Lazenka MF, Negus SS et al (2016) Abuse-related neurochemical effects of para-substituted methcathinone analogs in rats: microdialysis studies of nucleus accumbens dopamine and serotonin. J Pharmacol Exp Ther 356(1):182–190PubMedPubMedCentralGoogle Scholar
  149. Suzuki M, Deschamps JR, Jacobson AE, Rice KC (2015) Chiral resolution and absolute configuration of the enantiomers of the psychoactive “designer drug” 3,4-methylenedioxypyrovalerone. Chirality 27(4):287–293PubMedPubMedCentralGoogle Scholar
  150. Thomae K (1963) α-Pyrrolidino-ketones. Dr. Karl Thomae GmbH, Biberach an der Riss, Germany. GB 933507Google Scholar
  151. United Nations Office on Drugs and Crime (UNODC) (2017) Market analysis of synthetic drugs. Amphetamine-type stimulants, new psychoactive substances. World Drug Report 2017. Booklet 4. Vienna, Austria. https://www.unodc.org/wdr2017/field/Booklet_4_ATSNPS.pdf. Accessed 8 Sep 2018
  152. van der Schoot J, Ariens EJ, van Rossum J, Hurkmans JA (1962) Phenylisopropylamine derivatives, structure and action. Arzneimittelforschung 12:902–907PubMedGoogle Scholar
  153. Vandewater SA, Creehan KM, Taffe MA (2015) Intravenous self-administration of entactogen-class stimulants in male rats. Neuropharmacology 99:538–545PubMedPubMedCentralGoogle Scholar
  154. Vaugeois JM, Bonnet JJ, Duterte-Boucher D, Costentin J (1993) In vivo occupancy of the striatal dopamine uptake complex by various inhibitors does not predict their effects on locomotion. Eur J Pharmacol 230(2):195–201PubMedGoogle Scholar
  155. Volkow ND, Morales M (2015) The brain on drugs: from reward to addiction. Cell 162(4):712–725PubMedGoogle Scholar
  156. Warrick BJ, Hill M, Hekman K, Christensen R, Goetz R, Casavant MJ et al (2013) A 9-state analysis of designer stimulant, “bath salt,” hospital visits reported to poison control centers. Ann Emerg Med 62(3):244–251PubMedGoogle Scholar
  157. Wander A (1963) α-Pyrrolidino-valerophenones. Dr. A. Wander S.A., Bern, Switzerland. GB 927475Google Scholar
  158. Watterson LR, Hood L, Sewalia K, Tomek SE, Yahn S, Johnson CT et al (2012) The reinforcing and rewarding effects of methylone, a synthetic cathinone commonly found in “bath salts.” J Addict Res Ther (Suppl 9). pii: 002Google Scholar
  159. Watterson LR, Kugahl PR, Nemirovsky NE, Sewalia K, Grabenauer M, Thomas BF et al (2014) Potent rewarding and reinforcing effects of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV). Addict Biol 19(2):165–174PubMedGoogle Scholar
  160. Watterson LR, Olive MF (2017) Reinforcing effects of cathinone NPS in the intravenous drug self-administration paradigm. Curr Top Behav Neurosci 32:133–143PubMedGoogle Scholar
  161. Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL (2005) Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs. J Pharmacol Exp Ther 313(2):848–854PubMedGoogle Scholar
  162. Wee S, Woolverton WL (2006) Self-administration of mixtures of fenfluramine and amphetamine by rhesus monkeys. Pharmacol Biochem Behav 84(2):337–343PubMedGoogle Scholar
  163. Willuhn I, Wanat MJ, Clark JJ, Phillips PE (2010) Dopamine signaling in the nucleus accumbens of animals self-administering drugs of abuse. Curr Top Behav Neurosci 3:29–71PubMedPubMedCentralGoogle Scholar
  164. Wojcieszak J, Andrzejczak D, Wojtas A, Golembiowska K, Zawilska JB (2018) Effects of the new generation of α-pyrrolidinophenones on spontaneous locomotor activities in mice, and on extracellular dopamine and serotonin levels in the mouse striatum. Forensic Toxicol 36(2):334–350PubMedPubMedCentralGoogle Scholar
  165. Wright MJ Jr, Angrish D, Aarde SM, Barlow DJ, Buczynski MW, Creehan KM et al (2012) Effect of ambient temperature on the thermoregulatory and locomotor stimulant effects of 4-methylmethcathinone in Wistar and Sprague-Dawley rats. PLoS One 7(8):e44652PubMedPubMedCentralGoogle Scholar
  166. Yan Y, Newman AH, Xu M (2014) Dopamine D1 an D3 receptors mediate reconsolidation of cocaine memories in mouse models of drug self-administration. Neuroscience 278:154–164PubMedPubMedCentralGoogle Scholar
  167. Zdrazil B, Hellsberg E, Viereck M, Ecker GF (2016) From linked open data to molecular interaction: studying selectivity trends for ligands of the human serotonin and dopamine transporter. Medchemcomm 7(9):1819–1831PubMedPubMedCentralGoogle Scholar
  168. Zolkowska D, Jain R, Rothman RB, Partilla JS, Roth BL, Setola V et al (2009) Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil. J Pharmacol Exp Ther 329(2):738–746PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Michael H. Baumann
    • 1
    Email author
  • Hailey M. Walters
    • 2
  • Marco Niello
    • 3
  • Harald H. Sitte
    • 3
  1. 1.Designer Drug Research Unit (DDRU) NIDA, IRP, NIHBaltimoreUSA
  2. 2.Developmental, Cognitive and Behavioral NeuroscienceUniversity of HoustonHoustonUSA
  3. 3.Center for Physiology and PharmacologyMedical University of ViennaViennaAustria

Personalised recommendations