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Locomotor effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in mice: psychostimulant effects, stereotypy, and sensitization

  • Michael D. Berquist
  • Sebastian Leth-Petersen
  • Jesper Langgaard Kristensen
  • William E. FantegrossiEmail author
Original Investigation

Abstract

Rationale

There is a renewed interest in the use of 3,4-methylenedioxymethamphetamine (MDMA) for treating psychiatric conditions. Although MDMA has entered phase II clinical trials and shows promise as an adjunct treatment, there is an extensive literature detailing the potential neurotoxicity and adverse neurobehavioral effects associated with MDMA use. Previous research indicates that the adverse effects of MDMA may be due to its metabolism into reactive catechols that can enter the brain and serve directly as neurotoxicants. One approach to mitigate MDMA’s potential for adverse effects is to reduce O-demethylation by deuterating the methylenedioxy ring of MDMA. There are no studies that have evaluated the effects of deuterating MDMA on behavioral outcomes.

Objectives

The purpose of the present study was to assess the motor-stimulant effects of deuterated MDMA (d2-MDMA) and compare them to MDMA in male mice.

Methods

Two experiments were performed to quantify mouse locomotor activity and to vary the drug administration regimen (single bolus administration or cumulative administration).

Results

The results of Experiments 1 and 2 indicate that d2-MDMA is less effective at eliciting horizontal locomotion than MDMA; however, the differences between the compounds diminish as the number of cumulative administrations increase. Both d2-MDMA and MDMA can elicit sensitized responses, and these effects cross-sensitize to the prototypical drug of abuse methamphetamine. Thus, d2-MDMA functions as a locomotor stimulant similar to MDMA, but, depending on the dosing regimen, may be less susceptible to inducing sensitization to stereotyped movements.

Conclusions

These findings indicate that d2-MDMA is behaviorally active and produces locomotor effects that are similar to MDMA, which warrant additional assessments of d2-MDMA’s behavioral and physiological effects to determine the conditions under which this compound may serve as a relatively safer alternative to MDMA for clinical use.

Keywords

3,4-Methylenedioxymethamphetamine MDMA Locomotor activity Sensitization Stereotypy Deuterium substitution Cumulative administration Cross-sensitization Methamphetamine 

Notes

Acknowledgements

The authors thank Lauren Russell and William Hyatt for assisting with surgeries.

Funding information

This research was funded by NIH grants DA022981 and GM110702, and DEA/FDA contract HHSF223201610079C. Racemic d2-MDMA hydrochloride was synthesized by Sebastian Leth-Petersen at the Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 København Ø, Denmark.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

213_2019_5380_MOESM1_ESM.pdf (1006 kb)
ESM 1 (PDF 1005 kb)
213_2019_5380_MOESM2_ESM.docx (1.4 mb)
ESM 2 (DOCX 1484 kb)

References

  1. Bai F, Lau SS, Monks TJ (1999) Glutathione and N-acetylcysteine conjugates of alpha-methyldopamine produce serotonergic neurotoxicity: possible role in methylenedioxyamphetamine-mediated neurotoxicity. Chem Res Toxicol 12:1150–1157CrossRefGoogle Scholar
  2. Bai F, Jones DC, Lau SS, Monks TJ (2001) Serotonergic neurotoxicity of 3,4-(+/-)-methylenedioxyamphetamine and 3,4-(+/-)-methylendioxymethamphetamine (ecstasy) is potentiated by inhibition of gamma-glutamyl transpeptidase. Chem Res Toxicol 14:863–870CrossRefGoogle Scholar
  3. Baladi MG, Koek W, Aumann M, Velasco F, France CP (2012) Eating high fat chow enhances the locomotor-stimulating effects of cocaine in adolescent and adult female rats. Psychopharmacology (Berl) 222:447–457.  https://doi.org/10.1007/s00213-012-2663-7 CrossRefGoogle Scholar
  4. Ball KT, Klein JE, Plocinski JA, Slack R (2011) Behavioral sensitization to 3,4-methylenedioxymethamphetamine is long-lasting and modulated by the context of drug administration. Behav Pharmacol 22:847–850.  https://doi.org/10.1097/FBP.0b013e32834d13b4 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bexis S, Docherty JR (2006) Effects of MDMA, MDA and MDEA on blood pressure, heart rate, locomotor activity and body temperature in the rat involve alpha-adrenoceptors. Br J Pharmacol 147:926–934CrossRefGoogle Scholar
  6. Carvalho M, Milhazes N, Remião F, Borges F, Fernandes E, Amado F, Monks TJ, Carvalho F, Bastos ML (2004) Hepatotoxicity of 3,4-methylenedioxyamphetamine and alpha-methyldopamine in isolated rat hepatocytes: formation of glutathione conjugates. Arch Toxicol 78:16–24.  https://doi.org/10.1007/s00204-003-0510-7 CrossRefPubMedGoogle Scholar
  7. Chu T, Kumagai Y, DiStefano EW, Cho AK (1996) Disposition of methylenedioxymethamphetamine and three metabolites in the brains of different rat strains and their possible roles in acute serotonin depletion. Biochem Pharmacol 51:789–796CrossRefGoogle Scholar
  8. Claassen DO, Carroll B, De Boer LM, Wu E, Ayyagari R, Gandhi S, Stamler D (2017) Indirect tolerability comparison of Deutetrabenazine and Tetrabenazine for Huntington disease. J Clin Mov Disord 4:3-017-0051-5. eCollection 2017.  https://doi.org/10.1186/s40734-017-0051-5 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Commins DL, Vosmer G, Virus RM, Woolverton WL, Schuster CR, Seiden LS (1987) Biochemical and histological evidence that methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain. J Pharmacol Exp Ther 241:338–345PubMedGoogle Scholar
  10. Creighton FJ, Black DL, Hyde CE (1991) ‘Ecstasy’ psychosis and flashbacks. Br J Psychiatry 159:713–715CrossRefGoogle Scholar
  11. Dafters RI (1995) Hyperthermia following MDMA administration in rats: effects of ambient temperature, water consumption, and chronic dosing. Physiol Behav 58:877–882CrossRefGoogle Scholar
  12. de la Torre R, Farré M (2004) Neurotoxicity of MDMA (ecstasy): the limitations of scaling from animals to humans. Trends Pharmacol Sci 25:505–508.  https://doi.org/10.1016/j.tips.2004.08.001 CrossRefGoogle Scholar
  13. de la Torre R, Farré M, Roset P, Pizarro N, Abanades S, Segura M, Segura J, Camí J (2004) Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition. Ther Drug Monit 26:137–144Google Scholar
  14. Dean M, Sung VW (2018) Review of deutetrabenazine: a novel treatment for chorea associated with Huntington’s disease. Drug Des Devel Ther 12:313–319.  https://doi.org/10.2147/DDDT.S138828 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Di lorio CR, Watkins TJ, Dietrich MS, Cao A, Blackford JU, Rogers B, Ansari MS, Baldwin RM, Li R, Kessler RM, Salomon RM, Benningfield M, Cowan RL (2012) Evidence for chronically altered serotonin function in the cerebral cortex of female 3,4-methylenedioxymethamphetamine polydrug users. Arch Gen Psychiatry 69:399–409.  https://doi.org/10.1001/archgenpsychiatry.2011.156 CrossRefGoogle Scholar
  16. Fantegrossi WE, Godlewski T, Karabenick RL, Stephens JM, Ullrich T, Rice KC, Woods JH (2003) Pharmacological characterization of the effects of 3,4-methylenedioxymethamphetamine ("ecstasy") and its enantiomers on lethality, core temperature, and locomotor activity in singly housed and crowded mice. Psychopharmacology 166:202–211.  https://doi.org/10.1007/s00213-002-1261-5 CrossRefPubMedGoogle Scholar
  17. Fantegrossi WE, Murai N, Mathuna BO, Pizarro N, de la Torre R (2009) Discriminative stimulus effects of 3,4-methylenedioxymethamphetamine and its enantiomers in mice: pharmacokinetic considerations. J Pharmacol Exp Ther 329:1006–1015.  https://doi.org/10.1124/jpet.109.150573 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Fantegrossi WE, Xiao WR, Zimmerman SM (2013) Novel technology for modulating locomotor activity as an operant response in the mouse: implications for neuroscience studies involving "exercise" in rodents. J Neurosci Methods 212:338–343.  https://doi.org/10.1016/j.jneumeth.2012.10.020 CrossRefPubMedGoogle Scholar
  19. Food and Drug Administration (FDA) (2017) Assessment of abuse potential of drugs: guidance for industry. Accessed 12/6/18 from https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
  20. Henry JA (1992) Ecstasy and the dance of death. BMJ 305:5–6CrossRefGoogle Scholar
  21. Huntington Study Group, Frank S, Testa CM, Stamler D, Kayson E, Davis C, Edmondson MC et al (2016) Effect of deutetrabenazine on chorea among patients with Huntington disease: a randomized clinical trial. JAMA 316:40–50.  https://doi.org/10.1001/jama.2016.8655 CrossRefGoogle Scholar
  22. Itzhak Y, Ali SF, Achat CN, Anderson KL (2003) Relevance of MDMA (“ecstasy”)-induced neurotoxicity to long-lasting psychomotor stimulation in mice. Psychopharmacology 166:241–248.  https://doi.org/10.1007/s00213-002-1320-y CrossRefPubMedGoogle Scholar
  23. Kalivas PW, Duffy P, White SR (1998) MDMA elicits behavioral and neurochemical sensitization in rats. Neuropsychopharmacology 18:469–479CrossRefGoogle Scholar
  24. Li JX, Shah AP, Patel SK, Rice KC, France CP (2013) Modification of the behavioral effects of morphine in rats by serotonin 5-HT(1)A and 5-HT(2)A receptor agonists: antinociception, drug discrimination, and locomotor activity. Psychopharmacology 225:791–801.  https://doi.org/10.1007/s00213-012-2870-2 CrossRefPubMedGoogle Scholar
  25. McGuire BA, Baladi MG, France CP (2011) Eating high-fat chow enhances sensitization to the effects of methamphetamine on locomotion in rats. Eur J Pharmacol 658:156–159.  https://doi.org/10.1016/j.ejphar.2011.02.027 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Miller RT, Lau SS, Monks TJ (1996) Effects of intracerebroventricular administration of 5-(glutathion-S-yl)-alpha-methyldopamine on brain dopamine, serotonin, and norepinephrine concentrations in male Sprague-Dawley rats. Chem Res Toxicol 9:457–465.  https://doi.org/10.1021/tx9501546 CrossRefPubMedGoogle Scholar
  27. Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Doblin R (2011) The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. J Psychopharmacol 25:439–452.  https://doi.org/10.1177/0269881110378371 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Mithoefer MC, Mithoefer AT, Feduccia AA, Jerome L, Wagner M, Wymer J, Holland J, Hamilton S, Yazar-Klosinski B, Emerson A, Doblin R (2018) 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psychiatry 5:486–497CrossRefGoogle Scholar
  29. Morgan MJ (2000) Ecstasy (MDMA): a review of its possible persistent psychological effects. Psychopharmacology 152:230–248CrossRefGoogle Scholar
  30. Mullard A (2016) Deuterated drugs draw heavier backing. Nat Rev Drug Discov 15:219–221.  https://doi.org/10.1038/nrd.2016.63 CrossRefPubMedGoogle Scholar
  31. National Research Council (2011) Guide for the care and use of laboratory animals, 8th edn. Washington, DC: The National Academies Press.  https://doi.org/10.17226/12910.
  32. Ortuño J, Pizarro N, Farré M, Mas M, Segura J, Camí J, Brenneisen R, de la Torre R (1999) Quantification of 3,4-methylenedioxymetamphetamine and its metabolites in plasma and urine by gas chromatography with nitrogen-phosphorus detection. J Chromatogr B Biomed Sci Appl 723:221–232CrossRefGoogle Scholar
  33. Ot’alora GM, Grigsby J, Poulter B, Van Derveer JW 3rd, Giron SG, Jerome L, Feduccia AA, Hamilton S, Yazar-Klosinski B, Emerson A, Mithoefer MC, Doblin R (2018) 3,4-Methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress disorder: a randomized phase 2 controlled trial. J Psychopharmacol 32:1295–1307.  https://doi.org/10.1177/0269881118806297 CrossRefGoogle Scholar
  34. Reneman L, Endert E, de Bruin K, Lavalaye J, Feenstra MG, de Wolff FA, Booij J (2002) The acute and chronic effects of MDMA (“ecstasy”) on cortical 5-HT2A receptors in rat and human brain. Neuropsychopharmacology 26(3):387–396.  https://doi.org/10.1016/S0893-133X(01)00366-9 CrossRefPubMedGoogle Scholar
  35. Ricaurte GA, DeLanney LE, Irwin I, Langston JW (1988) Toxic effects of MDMA on central serotonergic neurons in the primate: importance of route and frequency of drug administration. Brain Res 446:165–168.  https://doi.org/10.1016/0006-8993(88)91309-1 CrossRefPubMedGoogle Scholar
  36. Schifano F (1991) Chronic atypical psychosis associated with MDMA (“ecstasy”) abuse. Lancet 338:1335CrossRefGoogle Scholar
  37. Segura M, Ortuno J, Farre M, McLure JA, Pujadas M, Pizarro N, Llebaria A, Joglar J, Roset PN, Segura J, de la Torre R (2001) 3,4-Dihydroxymethamphetamine (HHMA). A major in vivo 3,4-methylenedioxymethamphetamine (MDMA) metabolite in humans. Chem Res Toxicol 14:1203–1208CrossRefGoogle Scholar
  38. Spanos LJ, Yamamoto BK (1989) Acute and subchronic effects of methylenedioxymethamphetamine [(+/-)MDMA] on locomotion and serotonin syndrome behavior in the rat. Pharmacol Biochem Behav 32:835–840CrossRefGoogle Scholar
  39. Steketee JD, Kalivas PW (2011) Drug wanting: behavioral sensitization and relapse to drug-seeking behavior. Pharmacol Rev 63:348–365.  https://doi.org/10.1124/pr.109.001933 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Stone DM, Hanson GR, Gibb JW (1987a) Differences in the central serotonergic effects of methylenedioxymethamphetamine (MDMA) in mice and rats. Neuropharmacology 26:1657–1661CrossRefGoogle Scholar
  41. Stone DM, Merchant KM, Hanson GR, Gibb JW (1987b) Immediate and long-term effects of 3,4-methylenedioxymethamphetamine on serotonin pathways in brain of rat. Neuropharmacology 26:1677–1683CrossRefGoogle Scholar
  42. Thal SB, Lommen MJJ (2018) Current Perspective on MDMA-Assisted Psychotherapy for Posttraumatic Stress Disorder. J Contemp Psychother 48:99–108.  https://doi.org/10.1007/s10879-017-9379-2 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Thorn DA, Jing L, Qiu Y, Gancarz-Kausch AM, Galuska CM, Dietz DM, Zhang Y, Li JX (2014) Effects of the trace amine-associated receptor 1 agonist RO5263397 on abuse-related effects of cocaine in rats. Neuropsychopharmacology 39:2309–2316.  https://doi.org/10.1038/npp.2014.91 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Wareing M, Fisk JE, Murphy PN (2000) Working memory deficits in current and previous users of MDMA (‘ecstasy’). Br J Psychol 91(Pt 2):181–188CrossRefGoogle Scholar
  45. Yeh SY, Hsu FL (1991) The neurochemical and stimulatory effects of putative metabolites of 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine in rats. Pharmacol Biochem Behav 39:787–790CrossRefGoogle Scholar
  46. Young R, Glennon RA (2008) MDMA (N-methyl-3,4-methylenedioxyamphetamine) and its stereoisomers: similarities and differences in behavioral effects in an automated activity apparatus in mice. Pharmacol Biochem Behav 88:318–331CrossRefGoogle Scholar
  47. Zhang Z, Tang W (2018) Drug metabolism in drug discovery and development. Acta Pharm Sin B 8:721–732.  https://doi.org/10.1016/j.apsb.2018.04.003 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Michael D. Berquist
    • 1
  • Sebastian Leth-Petersen
    • 2
  • Jesper Langgaard Kristensen
    • 2
  • William E. Fantegrossi
    • 1
    Email author
  1. 1.Department of Pharmacology and Toxicology, College of MedicineUniversity of Arkansas for Medical SciencesLittle RockUSA
  2. 2.Department of Drug Design and Pharmacology, Faculty of Health and Medical SciencesUniversity of CopenhagenKøbenhavn ØDenmark

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