Skip to main content
SpringerLink
Log in

Abuse potential of methylenedioxymethamphetamine (MDMA) and its derivatives in zebrafish: role of serotonin 5HT2-type receptors

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

An Erratum to this article was published on 26 September 2016

Abstract

Rationale

The synthetic phenethylamines are recreational drugs known to produce psychostimulant effects. However, their abuse potential has not been widely studied.

Objectives

Here, we investigated the rewarding and the hallucinatory effects of 2,5-dimetoxy-4-bromo-amphetamine hydrobromide (DOB) and para-methoxyamphetamine (PMA) in comparison with the classical 3,4-methylenedioxymethamphetamine (MDMA). In addition, the role of serotonin 5-HT2-like receptor on the abovementioned effects was evaluated.

Methods

Zebrafish were intramuscularly (i.m.) treated with a wide range of doses of DOB (0.1–20 mg/kg), PMA (0.0005–2 mg/kg), or MDMA (0.5–160 mg/kg). Animals were submitted to a conditioned place preference (CPP) task, to investigation of the rewarding properties, and to the evaluation of hallucinatory behavior in terms of appearance of a trance-like behavior. The serotonin 5-HT2 subtype receptor antagonist ritanserin (0.025–2.5 mg/kg) in association with the maximal effective dose of MDMA, DOB, and PMA was given i.m., and the effect on CPP or hallucinatory behavior was evaluated.

Results

MDMA and its derivatives exhibited CPP in a biphasic fashion, being PMA the most potent. This effect was accompanied, for DOB (2 mg/kg) and PMA (0.1 mg/kg), by a trance-like hallucinatory behavior. MDMA at a high dose as 160 mg/kg did not induce any hallucinatory behavior. Ritanserin significantly blocked the rewarding and hallucinatory effects suggesting the involvement of serotonin 5HT2 subtype receptor.

Conclusion

Collectively, these findings demonstrate for the first time that the rewarding properties of DOB and PMA are accompanied by hallucinatory behavior through a serotonergic system and reinforce zebrafish as an emerging experimental model for screening new hallucinogens.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Aguilar MA, Rodríguez-Arias M, Miñarro J (2009) Neurobiological mechanisms of the reinstatement of drug-conditioned place preference. Brain Res Rev 59:253–277

    Article  PubMed  Google Scholar 

  • Araújo AM, Carvalho F, Bastos Mde L, Guedes de Pinho P, Carvalho M (2015) The hallucinogenic world of tryptamines: an updated review. Arch Toxicol 89:1151–1173

    Article  PubMed  Google Scholar 

  • Balíková M (2005) Nonfatal and fatal DOB (2,5-dimethoxy-4-bromoamphetamine) overdose. Forensic Sci Int 153:85–91

    Article  PubMed  Google Scholar 

  • Baylen CA, Rosenberg H (2006) A review of the acute subjective effects of MDMA/ecstasy. Addiction 101:933–947

    Article  PubMed  Google Scholar 

  • Benneyworth MA, Smith RL, Barrett RJ, Sanders-Bush E (2005) Complex discriminative stimulus properties of (+)lysergic acid diethylamide (LSD) in C57Bl/6J mice. Psychopharmacology (Berl) 179:854–862

    Article  CAS  Google Scholar 

  • Bilsky EJ, Montegut MJ, Nichols ML, Reid LD (1998) CGS 10746B, a novel dopamine release inhibitor, blocks the establishment of cocaine and MDMA conditioned place preferences. Pharmacol Biochem Behav 59:215–220

    Article  CAS  PubMed  Google Scholar 

  • Boehmler W, Obrecht-Pflumio S, Canfield V, Thisse C, Thisse B, Levenson R (2004) Evolution and expression of D2 and D3 dopamine receptor genes in zebrafish. Dev Dyn 230:481–493

    Article  CAS  PubMed  Google Scholar 

  • Braida D, Limonta V, Pegorini S, Zani A, Guerini-Rocco C, Gori E, Sala M (2007) Hallucinatory and rewarding effect of salvinorin A in zebrafish: kappa-opioid and CB1-cannabinoid receptor involvement. Psychopharmacology (Berl) 190:441–448

    Article  CAS  Google Scholar 

  • Braida D, Donzelli A, Martucci R, Capurro V, Busnelli M, Chini B, Sala M (2012) Neurohypophyseal hormones manipulation modulate social and anxiety-related behavior in zebrafish. Psychopharmacology (Berl) 220:319–323

    Article  CAS  Google Scholar 

  • Brennan KA, Carati C, Lea RA, Fitzmaurice PS, Schenk S (2009) Effect of D1-like and D2-like receptor antagonists on methamphetamine and 3,4-methylenedioxymethamphetamine self-administration in rats. Behav Pharmacol 20:688–694

    Article  CAS  PubMed  Google Scholar 

  • Cadoni C, Solinas M, Pisanu A, Zernig G, Acquas E, Di Chiara G (2005) Effect of 3,4-methylendioxymethamphetamine (MDMA, “ecstasy”) on dopamine transmission in the nucleus accumbens shell and core. Brain Res 1055:143–148

    Article  CAS  PubMed  Google Scholar 

  • Cheng KC, Xin X, Clark DP, La Riviere P (2011) Whole-animal imaging, gene function, and the Zebrafish Phenome Project. Curr Opin Genet Dev 21:620–629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collier AD, Khan KM, Caramillo EM, Mohn RS, Echevarria DJ (2014) Zebrafish and conditioned place preference: a translational model of drug reward. Prog Neuropsychopharmacol Biol Psychiatry 55:16–25

    Article  CAS  PubMed  Google Scholar 

  • Cunningham CL, Noble D (1992) Methamphetamine-induced conditioned place preference or aversion depending on dose and presence of drug. Ann NY Acad Sci 654:431–633

    Article  CAS  PubMed  Google Scholar 

  • Daniela E, Brennan K, Gittings D, Hely L, Schenk S (2004) Effect of SCH 23390 on (+/−)-3,4-methylenedioxymethamphetamine hyperactivity and self-administration in rats. Pharmacol Biochem Behav 77:745–750

    Article  CAS  PubMed  Google Scholar 

  • Daws LC, Irvine RJ, Callaghan PD, Toop NP, White JM, Bochner F (2000) Differential behavioural and neurochemical effects of para-methoxy-amphetamine and 3,4-methylenedioxy methamphetamine in the rat. Prog Neuropsychopharmacol Biol Psychiatry 24:955–977

    Article  CAS  PubMed  Google Scholar 

  • Daza-Losada M, Ribeiro Do Couto B, Manzanedo C, Aguilar MA, Rodríguez-Arias M, Miñarro J (2007) Rewarding effects and reinstatement of MDMA-induced CPP in adolescent mice. Neuropsychopharmacology 32:1750–1759

    Article  CAS  PubMed  Google Scholar 

  • de la Torre R, Farré M, Roset PN, Pizarro N, Abanades S, Segura M, Segura J, Camí J (2004) Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition. Ther Drug Monit 26:137–144

    Article  PubMed  Google Scholar 

  • Diller AJ, Rocha A, Cardon AL, Valles R, Wellman PJ, Nation JR (2007) The effects of concurrent administration of +/−3,4-methylenedioxymethamphetamine and cocaine on conditioned place preference in the adult male rat. Pharmacol Biochem Behav 88:165–170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dumont GJ, Verkes RJ (2006) A review of acute effects of 3,4-methylenedioxymethamphetamine in healthy volunteers. J Psychopharmacol 20:176–187

    Article  CAS  PubMed  Google Scholar 

  • Escobedo I, O’Shea E, Orio L, Sanchez V, Segura M, de la Torre R, Farre M, Green AR, Colado MI (2005) A comparative study on the acute and long-term effects of MDMA and 3,4-dihydroxymethamphetamine (HHMA) on brain monoamine levels after i.p. or striatal administration in mice. Br J Pharmacol 144:231–241

    Article  CAS  PubMed  Google Scholar 

  • European Monitoring Centre for Drugs and Drug Addiction (2003) Report on the risk assessment of PMMA in the framework of the joint action on new synthetic drugs. Office for Official Publications of the European Communities, Luxembourg

    Google Scholar 

  • Fantegrossi WE, Simoneau J, Cohen MS, Zimmerman SM, Henson CM, Rice KC, Woods JH (2010) Interaction of 5-HT2A and 5-HT2C receptors in R(−)-2,5-dimethoxy-4-iodoamphetamine-elicited head twitch behavior in mice. J Pharmacol Exp Ther 335:728–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 38:563–573

    Article  CAS  PubMed  Google Scholar 

  • García-Pardo MP, Escobar-Valero C, Rodríguez-Arias M, Miñarro J, Aguilar MA (2015) Involvement of NMDA glutamate receptors in the acquisition and reinstatement of the conditioned place preference induced by MDMA. Behav Pharmacol 26:411–417

    Article  PubMed  Google Scholar 

  • Gołembiowska K, Jurczak A, Kamińska K, Noworyta-Sokołowska K, Górska A (2016) Effect of some psychoactive drugs used as ‘legal highs’ on brain neurotransmitters. Neurotox Res 29:394–407

    Article  PubMed  Google Scholar 

  • Green AR, Mechan AO, Elliott JM, O’Shea E, Colado MI (2003) The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol Rev 55:463–508

    Article  CAS  PubMed  Google Scholar 

  • Harris DS, Baggott M, Mendelson JH, Mendelson JE, Jones RT (2002) Subjective and hormonal effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology (Berl) 162:396–405

    Article  CAS  Google Scholar 

  • Hill SL, Thomas SH (2011) Clinical toxicology of newer recreational drugs. Clin Toxicol (Phila) 49:705–719

    Article  CAS  Google Scholar 

  • Huang PK, Aarde SM, Angrish D, Houseknecht KL, Dickerson TJ, Taffe MA (2012) Contrasting effects of d-methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxy-pyrovalerone, and 4-methylmethcathinone on wheel activity in rats. Drug Alcohol Depend 126:168–175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kankaanpää A, Meririnne E, Lillsunde P, Seppälä T (1998) The acute effects of amphetamine derivatives on extracellular serotonin and dopamine levels in rat nucleus accumbens. Pharmacol Biochem Behav 59:1003–1009

    Article  PubMed  Google Scholar 

  • Koob GF, Le Moal M (2001) Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24:97–129

    Article  CAS  PubMed  Google Scholar 

  • Kravitz AV, Tye LD, Kreitzer AC (2012) Distinct roles for direct and indirect pathway striatal neurons in reinforcement. Nat Neurosci 15:816–818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lamb RJ, Griffiths RR (1987) Self-injection of d,1-3,4-methylenedioxy methamphetamine (MDMA) in the baboon. Psychopharmacology (Berl) 91:268–272

    Article  CAS  Google Scholar 

  • Lawn W, Barratt M, Williams M, Horne A, Winstock A (2014) The NBOMe hallucinogenic drug series: patterns of use, characteristics of users and self-reported effects in a large international sample. J Psychopharmacol 28:780–788

    Article  CAS  PubMed  Google Scholar 

  • Li P, Shah S, Huang L, Carr AL, Gao Y, Thisse C, Thisse B, Li L (2007) Cloning and spatial and temporal expression of the zebrafish dopamine D1 receptor. Dev Dyn 236:1339–1346

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  • Monte AP, Waldman SR, Marona-Lewicka D, Wainscott DB, Nelson DL, Sanders-Bush E, Nichols DE (1997) Dihydrobenzofuran analogues of hallucinogens. 4. Mescaline derivatives. J Med Chem 40:2997–3008

    Article  CAS  PubMed  Google Scholar 

  • Müller CP, Homberg JR (2015) Serotonin revisited. Behav Brain Res 277:1–2

    Article  PubMed  Google Scholar 

  • Neelkantan N, Mikhaylova A, Stewart AM, Arnold R, Gjeloshi V, Kondaveeti D, Poudel MK, Kalueff AV (2013) Perspectives on zebrafish models of hallucinogenic drugs and related psychotropic compounds. ACS Chem 4:1137–1150

    CAS  Google Scholar 

  • Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181

    Article  CAS  PubMed  Google Scholar 

  • Nichols DE (2016) Psychedelics. Pharmacol Rev 68:264–355

    Article  PubMed  Google Scholar 

  • O’Shea E, Escobedo I, Orio L, Sanchez V, Navarro M, Green AR, Colado MI (2005) Elevation of ambient room temperature has differential effects on MDMA-induced 5-HT and dopamine release in striatum and nucleus accumbens of rats. Neuropsychopharmacology 30:1312–1323

    Article  PubMed  Google Scholar 

  • Owens MJ, Knight DL, Ritchie JC, Nemeroff CB (1991) The 5-hydroxy-tryptamine 2 agonist, (±)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane stimulates the hypothalamic-pituitary-adrenal (HPA) axis. II. Biochemical and physiological evidence for the development of tolerance after chronic administration. J Pharmacol Exp Ther 256:787–794

    CAS  PubMed  Google Scholar 

  • Parrott AC (2013) Human psychobiology of MDMA or ‘Ecstasy’: an overview of 25 years of empirical research. Hum Psychopharmacol 28:289–307

    Article  CAS  PubMed  Google Scholar 

  • Parrott AC, Gibbs A, Scholey AB, King R, Owens K, Swann P, Ogden E, Stough C (2011a) MDMA and methamphetamine: some paradoxical negative and positive mood changes in an acute dose laboratory study. Psychopharmacology 215:527–536

    Article  CAS  PubMed  Google Scholar 

  • Parrott AC, Evans LJ, Howells J, Robart R (2011b) Cocaine versus Ecstasy/ MDMA: comparative effects on mood and cognition in recreational users. Open Addict J 4:36–37

    Article  Google Scholar 

  • Ponzoni L, Braida D, Pucci L, Andrea D, Fasoli F, Manfredi I, Papke RL, Stokes C, Cannazza G, Clementi F, Gotti C, Sala M (2014) The cytisine derivatives, CC4 and CC26, reduce nicotine-induced conditioned place preference in zebrafish by acting on heteromeric neuronal nicotinic acetylcholine receptors. Psychopharmacology (Berl) 231:4681–4693

    Article  CAS  Google Scholar 

  • Ribeiro Do Couto B, Daza-Losada M, Rodríguez-Arias M, Nadal R, Guerri C, Summavielle T, Miñarro J, Aguilar MA (2012) Adolescent pre-exposure to ethanol and 3,4-methylenedioxymethylamphetamine (MDMA) increases conditioned rewarding effects of MDMA and drug-induced reinstatement. Addict Biol 17:588–600

    Article  CAS  PubMed  Google Scholar 

  • Robertson JL, Savin NE, Preisler HK, Russell RM (1992) Pesticide bioassays with arthropods. CRC Press, Boca Raton

    Google Scholar 

  • Robledo P, Mendizabal V, Ortuño J, de la Torre R, Kieffer BL, Maldonado R (2004) The rewarding properties of MDMA are preserved in mice lacking mu-opioid receptors. Eur J Neurosci 20:853–858

    Article  PubMed  Google Scholar 

  • Rodríguez-Arias M, Manzanedo C, Roger-Sánchez C, Do Couto BR, Aguilar MA, Miñarro J (2010) Effect of adolescent exposure to WIN 55212–2 on the acquisition and reinstatement of MDMA-induced conditioned place preference. Prog Neuropsychopharmacol Biol Psychiatry 34:166–171

    Article  PubMed  Google Scholar 

  • Roger-Sánchez C, Rodríguez-Arias M, Miñarro J, Aguilar MA (2013a) Effects of risperidone on the acquisition and reinstatement of the conditioned place preference induced by MDMA. Brain Res Bull 98:36–43

    Article  PubMed  Google Scholar 

  • Roger-Sánchez C, Rodríguez-Arias M, Miñarro J, Aguilar MA (2013b) Involvement of 5-hydroxytryptamine 5-HT3 serotonergic receptors in the acquisition and reinstatement of the conditioned place preference induced by MDMA. Eur J Pharmacol 714:132–141

    Article  PubMed  Google Scholar 

  • Roger-Sánchez C, Aguilar MA, Manzanedo C, Miñarro J, Rodríguez-Arias M (2013c) Neurochemical substrates of MDMA reward: effects of the inhibition of serotonin reuptake on the acquisition and reinstatement of MDMA-induced CPP. Curr Pharm Des 19:7050–7064

    Article  PubMed  Google Scholar 

  • Schenk S, Gittings D, Colussi-Mas J (2011) Dopaminergic mechanisms of reinstatement of MDMA-seeking behaviour in rats. Br J Pharmacol 162:1770–1780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schneider H, Fritzky L, Williams J, Heumann C, Yochum M, Pattar K, Noppert G, Mock V, Hawley E (2012) Cloning and expression of a zebrafish 5-HT2C receptor gene. Gene 502:108–117

    Article  CAS  PubMed  Google Scholar 

  • Stewart A, Riehl R, Wong K, Green J, Cosgrove J, Vollmer K, Kyzar E, Hart P, Allain A, Cachat J, Gaikwad S, Hook M, Rhymes K, Newman A, Utterback E, Chang K, Kalueff AV (2011) Behavioral effects of MDMA (“Ecstasy”) on adult zebrafish. Behav Pharmacol 22:275–280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Streisinger G (2000) The zebrafish book. Oregon Press, Eugene

    Google Scholar 

  • Tran S, Nowicki M, Muraleetharan A, Gerlai R (2015) Differential effects of dopamine D1 and D 2/3 receptor antagonism on motor responses. Psychopharmacology (Berl) 232:795–806

    Article  CAS  Google Scholar 

  • Tzschentke TM (2007) Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol 12:227–462

    Article  CAS  PubMed  Google Scholar 

  • United Nations Office on Drugs and Crime (2015) World drug report. United Nations publication, Vienna

    Google Scholar 

  • Vandewater SA, Creehan KM, Taffe MA (2015) Intravenous self-administration of entactogen-class stimulants in male rats. Neuropharmacology 99:538–545

    Article  CAS  PubMed  Google Scholar 

  • Vidal-Infer A, Roger-Sánchez C, Daza-Losada M, Aguilar MA, Miñarro J, Rodríguez-Arias M (2012) Role of the dopaminergic system in the acquisition, expression and reinstatement of MDMA-induced conditioned place preference in adolescent mice. PLoS One 7(8), e43107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Winkelman M (1991) Therapeutic effects of hallucinogens. Anthropol Conscious 2:15–19

    Article  Google Scholar 

  • Winter JC (1984) The stimulus properties of p-methoxyamphetamine: a nonessential serotonergic component. Pharmacol Biochem Behav 20:201–203

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was partially supported by Fondazione Zardi-Gori (Milan, Italy).

Author information

Authors and Affiliations

  1. Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università degli Studi di Milano, Milan, Italy

    Luisa Ponzoni, Braida Daniela & Mariaelvina Sala

  2. Institute of Neuroscience, Consiglio Nazionale delle Ricerche (CNR), Milan, Italy

    Mariaelvina Sala

  3. Institute of Neuroscience, Consiglio Nazionale delle Ricerche, and Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università degli Studi di Milano, Via Vanvitelli 32, 20129, Milan, Italy

    Mariaelvina Sala

Authors
  1. Luisa Ponzoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Braida Daniela
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mariaelvina Sala
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mariaelvina Sala.

Ethics declarations

The experiments were performed in compliance with the recommendations of the European Community Council Directive No. 86/609/EEC and the subsequent Italian Law on the Protection of animals used for experimental and other scientific reasons. The experimental protocol was approved by the Italian Governmental Decree No. 18/2013. All efforts were made to minimize the number of animals used and their discomfort.

Conflict of interest

The authors do not declare any conflict of interest.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s00213-016-4433-4.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Video S1

Trance-like effect following PMA (0.1 mg/kg) evaluated within 5 min after treatment. (MP4 4162 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ponzoni, L., Daniela, B. & Sala, M. Abuse potential of methylenedioxymethamphetamine (MDMA) and its derivatives in zebrafish: role of serotonin 5HT2-type receptors. Psychopharmacology 233, 3031–3039 (2016). https://doi.org/10.1007/s00213-016-4352-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-016-4352-4

Keywords

Search

Navigation