Changes in dopamine, serotonin and their metabolites in brain microdialysates from rats following exposure to new psychoactive drugs

Abstract

New psychoactive drugs (NPDs), or so-called “designer drugs” are chemically transformed compounds of traditional drugs of abuse for the purpose of evading crackdown. The abuse of NPDs is a significant social problem and threatens public health; however, few studies on their effects on the central nervous system have been conducted. Microdialysis is a useful in vivo sampling technique in neurochemistry because it enables monitoring of synaptic release of neurotransmitters by drug exposure or other stimuli in real time. Dopamine (DA) and serotonin (5-HT) are important neurotransmitters associated with drug abuse and addiction. In this study, changes of DA, 5-HT and their metabolites in brain microdialysates from rats following exposure to selected 11 NPDs (MPA, 5-APDB, PCA, α-PVT, AB-PINACA, QUPIC, 5-fluoropentyl-3-pyridinoylindole, AMT, NMT, 4-OH-DET and desoxy-D2PM, 0.3, 1 and 3 mg/kg, consecutively, intraperitoneally) were investigated using a validated liquid chromatography –tandem mass spectrometry method. Most NPDs affected the extracellular levels of DA, 5-HT and/or their metabolites, showing consistent changes depending on the groups of chemical structures, such as amphetamines, synthetic cannabinoids and tryptamines. Significant DA and/or 5-HT increases were observed for all the amphetamine analogues. Weak fluctuations of DA and/or 5-HT concentrations were observed following exposure to synthetic cannabinoids and more severe fluctuations were shown by the tryptamines. The current results could be used as the preliminary data for further research concerning monoamine neurotransmitter-related mechanisms of NPDs. Moreover, the understanding gained from this research could be helpful to monitor the liability of NPD abuse and addiction.

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

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Liechti M (2015) Novel psychoactive substances (designer drugs): overview and pharmacology of modulators of monoamine signaling. Swiss Med Wkly 145:w14043

    PubMed  Google Scholar 

  2. 2.

    Zawilska JB, Andrzejczak D (2015) Next generation of novel psychoactive substances on the Horizon–a complex problem to face. Drug Alcohol Depend 157:1–17

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Anderzhanova E, Wotjak CT (2013) Brain microdialysis and its applications in experimental neurochemistry. Cell Tissue Res 354:27–39

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Boschi G, Scherrmann J (2000) Microdialysis in mice for drug delivery research. Adv Drug Deliv Rev 45:271–281

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Plock N, Kloft C (2005) Microdialysis—theoretical background and recent implementation in applied life-sciences. Eur J Pharm Sci 25:1–24

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Darvesh AS, Carroll RT, Geldenhuys WJ, Gudelsky GA, Klein J, Meshul CK, Van der Schyf CJ (2011) In vivo brain microdialysis: advances in neuropsychopharmacology and drug discovery. Expert Opin Drug Discov 6:109–127

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Chaurasia CS, Chen CE, Ashby CR Jr (1999) In vivo on-line HPLC-microdialysis: simultaneous detection of monoamines and their metabolites in awake freely-moving rats. J Pharm Biomed Anal 19:413–422

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Nirogi R, Komarneni P, Kandikere V, Boggavarapu R, Bhyrapuneni G, Benade V, Gorentla S (2013) A sensitive and selective quantification of catecholamine neurotransmitters in rat microdialysates by pre-column dansyl chloride derivatization using liquid chromatography-tandem mass spectrometry. J Chromatogr B 913-914:41–47

    CAS  Article  Google Scholar 

  9. 9.

    Greco S, Danysz W, Zivkovic A, Gross R, Stark H (2013) Microdialysate analysis of monoamine neurotransmitters—a versatile and sensitive LC–MS/MS method. Anal Chim Acta 771:65–72

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Cannazza G, Carrozzo MM, Cazzato AS, Bretis IM, Troisi L, Parenti C, Braghiroli D, Guiducci S, Zoli M (2012) Simultaneous measurement of adenosine, dopamine, acetylcholine and 5-hydroxytryptamine in cerebral mice microdialysis samples by LC–ESI-MS/MS. J Pharm Biomed Anal 71:183–186

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Parrot S, Neuzeret PC, Denoroy L (2011) A rapid and sensitive method for the analysis of brain monoamine neurotransmitters using ultra-fast liquid chromatography coupled to electrochemical detection. J Chromatogr B 879:3871–3878

    CAS  Article  Google Scholar 

  12. 12.

    Yoshitake T, Kehr J, Yoshitake S, Fujino K, Nohta H, Yamaguchi M (2004) Determination of serotonin, noradrenaline, dopamine and their metabolites in rat brain extracts and microdialysis samples by column liquid chromatography with fluorescence detection following derivatization with benzylamine and 1,2-diphenylethylenediamine. J Chromatogr B 807:177–183

    CAS  Article  Google Scholar 

  13. 13.

    Gingrich JA, Hen R (2001) Dissecting the role of the serotonin system in neuropsychiatric disorders using knockout mice. Psychopharmacology 155:1–10

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Hirao K, Pontone GM, Smith GS (2015) Molecular imaging of neuropsychiatric symptoms in Alzheimer’s and Parkinson’s disease. Neurosci Biobehav Rev 49:157–170

    Article  PubMed  Google Scholar 

  15. 15.

    Iversen L, White M, Treble R (2014) Designer psychostimulants: pharmacology and differences. Neuropharmacology 87:59–65

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Matsumoto T, Maeno Y, Kato H, Seko-Nakamura Y, Monma-Ohtaki J, Ishiba A, Nagao M, Aoki Y (2014) 5-Hydroxytryptamine- and dopamine-releasing effects of ring-substituted amphetamines on rat brain: a comparative study using in vivo microdialysis. Eur Neuropsychopharmacol 24:1362–1370

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Kehr J, Ichinose F, Yoshitake S, Goiny M, Sievertsson T, Nyberg F, Yoshitake T (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 164:1949–1958

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Kim M, Lee JG, Yang CH, Lee S (2016) Silica stationary phase-based on-line sample enrichment coupled with LC–MS/MS for the quantification of dopamine, serotonin and their metabolites in rat brain microdialysates. Anal Chim Acta 923:55–65

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Zhao RJ, Yoon SS, Lee BH, Kwon YK, Kim KJ, Shim I, Choi KH, Kim MR, Golden GT, Yang CH (2006) Acupuncture normalizes the release of accumbal dopamine during the withdrawal period and after the ethanol challenge in chronic ethanol-treated rats. Neurosci Lett 395:28–32

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Zaitsu K, Hayashi Y, Kusano M, Tsuchihashi H, Ishii A (2016) Application of metabolomics to toxicology of drugs of abuse: a mini review of metabolomics approach to acute and chronic toxicity studies. Drug Metab Pharmacokinet 31:21–26

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Welter-Luedeke J, Maurer HH (2016) New psychoactive substances: chemistry, pharmacology, metabolism, and detectability of amphetamine derivatives with modified ring systems. Ther Drug Monit 38:4–11

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    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 39:1–6

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    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 87:206–213

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Kolanos R, Sakloth F, Jain AD, Partilla JS, Baumann MH, Glennon RA (2015) Structural modification of the designer stimulant α-pyrrolidinovalerophenone (α-PVP) influences potency at dopamine transporters. ACS Chem Neurosci 6:1726–1731

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Monte AP, Marona-Lewicka D, Cozzi NV, Nichols DE (1993) Synthesis and pharmacological examination of benzofuran, indan, and tetralin analogues of 3,4-(methylenedioxy)amphetamine. J Med Chem 36:3700–3706

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Rickli A, Kopf S, Hoener MC, Liechti ME (2015) Pharmacological profile of novel psychoactive benzofurans. Br J Pharmacol 172:3412–3425

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Iversen L, Gibbons S, Treble R, Setola V, Huang XP, Roth BL (2013) Neurochemical profiles of some novel psychoactive substances. Eur J Pharmacol 700:147–151

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Johnson MP, Huang XM, Oberlender R, Nash JF, Nichols DE (1990) Behavioral, biochemical and neurotoxicological actions of the α-ethyl homologue of p-chloroamphetamine. Eur J Pharmacol 191:1–10

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Lanteri C, Salomon L, Torrens Y, Glowinski J, Tassin JP (2008) Drugs of abuse specifically sensitize noradrenergic and serotonergic neurons via a non-dopaminergic mechanism. Neuropsychopharmacology 33:1724–1734

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Saadat KS, Elliott JM, Colado MI, Green AR (2006) The acute and long-term neurotoxic effects of MDMA on marble burying behaviour in mice. J Psychopharmacol 20:264–271

    Article  PubMed  Google Scholar 

  31. 31.

    Murnane KS, Perrine SA, Finton BJ, Galloway MP, Howell LL, Fantegrossi WE (2012) Effects of exposure to amphetamine derivatives on passive avoidance performance and the central levels of monoamines and their metabolites in mice: correlations between behavior and neurochemistry. Psychopharmacology 220:495–508

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    De Luca MA, Bimpisidis Z, Melis M, Marti M, Caboni P, Valentini V, Margiani G, Pintori N, Polis I, Marsicano G, Parsons LH, Di Chiara G (2015) Stimulation of in vivo dopamine transmission and intravenous self-administration in rats and mice by JWH-018, a Spice cannabinoid. Neuropharmacology 99:705–714

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Ossato A, Canazza I, Trapella C, Vincenzi F, De Luca MA, Rimondo C, Varani K, Borea PA, Serpelloni G, Marti M (2016) Effect of JWH-250, JWH-073 and their interaction on "tetrad", sensorimotor, neurological and neurochemical responses in mice. Prog Neuropsychopharmacol Biol Psychiatry 67:31–50

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    De Luca MA, Castelli MP, Loi B, Porcu A, Martorelli M, Miliano C, Kellett K, Davidson C, Stair JL, Schifano F, Di Chiara G (2015) Native CB1 receptor affinity, intrinsic activity and accumbens shell dopamine stimulant properties of third generation SPICE/K2 cannabinoids: BB-22, 5F-PB-22, 5F-AKB-48 and STS-135. Neuropharmacology 105:630–638

    Article  PubMed  Google Scholar 

  35. 35.

    Blough BE, Landavazo A, Decker AM, Partilla JS, Baumann MH, Rothman RB (2014) Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes. Psychopharmacology 231:4135–4144

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Nagai F, Nonaka R, Satoh K, Kamimura H (2007) The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain. Eur J Pharmacol 559:132–137

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Arunotayanun W, Dalley JW, Huang XP, Setola V, Treble R, Iversen L, Roth BL, Gibbons S (2013) An analysis of the synthetic tryptamines AMT and 5-MeO-DALT: emerging novel psychoactive drugs. Bioorg Med Chem Lett 23:3411–3415

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Sakashita Y, Abe K, Katagiri N, Kambe T, Saitoh T, Utsunomiya I, Horiguchi Y, Taguchi K (2015) Effect of psilocin on extracellular dopamine and serotonin levels in the mesoaccumbens and mesocortical pathway in awake rats. Biol Pharm Bull 38:134–138

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Simmler LD, Rickli A, Schramm Y, Hoener MC, Liechti ME (2014) Pharmacological profiles of aminoindanes, piperazines, and pipradrol derivatives. Biochem Pharmacol 88:237–244

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Davidson C, Ramsey J (2012) Desoxypipradrol is more potent than cocaine on evoked dopamine efflux in the nucleus accumbens. J Psychopharmacol 26:1036–1041

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by a grant from the Ministry of Food and Drug Safety (14182MFDS979) and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2014R1A1A1036222).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Sooyeun Lee.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors. All experiments were carried out in accordance with the guidelines of the Institutional Animal Care and Use Committee at Daegu Haany University.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kim, M., Kim, D.H., Lee, Y.S. et al. Changes in dopamine, serotonin and their metabolites in brain microdialysates from rats following exposure to new psychoactive drugs. Forensic Toxicol 35, 66–76 (2017). https://doi.org/10.1007/s11419-016-0335-8

Download citation

Keywords

  • New psychoactive drugs
  • Synthetic cannabinoids
  • Dopamine
  • Serotonin
  • Microdialysis
  • LC–MS/MS