Skip to main content
SpringerLink
Log in

Behavioural and neurochemical effects of combined MDMA and THC administration in mice

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

Abstract

Rationale

Cannabis is the most widely consumed drug associated with 3,4-methylenedioxymethamphetamine (MDMA) use.

Objectives

This study examines whether low doses of MDMA and delta-9-tetrahydrocannabinol (THC) produce synergistic rewarding/reinforcing effects in mice using the conditioned place preference (CPP) and operant self-administration paradigms. Changes in dopamine (DA) outflow were monitored in the nucleus accumbens (NAC) after single or combined administration of these compounds.

Results

MDMA induced a significant CPP at the dose of 10 mg/kg but not at the dose of 3 mg/kg. THC (0.3 mg/kg) by itself was also ineffective in this paradigm. The combined administration of the low dose of MDMA (3 mg/kg) and THC (0.3 mg/kg) produced CPP, whereas the combination of MDMA (10 mg/kg) and THC (0.3 mg/kg) significantly decreased CPP. Animals treated with THC self-administered a sub-threshold dose of MDMA (0.06 mg/kg per infusion), while animals receiving vehicle did not. However, THC did not modify the self-administration of an effective dose of MDMA (0.125 mg/kg per infusion). In microdialysis studies, a low dose of THC significantly increased DA outflow in the NAC, while a low dose of MDMA did not. When MDMA was administered before THC, DA levels decreased with respect to THC. However, when THC was administered before MDMA, DA levels were not significantly modified with respect to THC.

Conclusions

These results demonstrate that a low dose of THC modifies in different ways (increases and decreases) the sensitivity of animals to the behavioural effects of MDMA and that THC and MDMA converge at a common mechanism modulating DA outflow in the NAC of mice.

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

  • Beardsley PM, Balster RL, Harris LS (1986) Self-administration of methylenedioxy-methamphetamine (MDMA) by rhesus monkeys. Drug Alcohol Depend 18:149–57

    Article  PubMed  CAS  Google Scholar 

  • Berrendero F, Maldonado R (2002) Involvement of the opioid system in the anxiolytic-like effects induced by delta(9)-tetrahydrocannabinol. Psychopharmacology 163:111–117

    Article  PubMed  CAS  Google Scholar 

  • Bilsky EJ, Reid LD (1991) MDL72222, a serotonin 5-HT3 receptor antagonist, blocks MDMA’s ability to establish a conditioned place preference. Pharmacol Biochem Behav 39:509–512

    Article  PubMed  CAS  Google Scholar 

  • Bilsky EJ, Hui Y, Hubbell CL, Reid LD (1990) Methylenedioxymethamphetamine’s capacity to establish place preferences and modify intake of an alcoholic beverage. Pharmacol Biochem Behav 37:633–638

    Article  PubMed  CAS  Google Scholar 

  • Braida D, Sala M (2002) Role of the endocannabinoid system in MDMA intracerebral self-administration in rats. Br J Pharmacol 136:1089–1092

    Article  PubMed  CAS  Google Scholar 

  • Braida D, Iosue S, Pegorini S, Sala M (2005) 3,4 Methylenedioxymethamphetamine-induced conditioned place preference (CPP) is mediated by endocannabinoid system. Pharmacol Res 51:177–182

    Article  PubMed  CAS  Google Scholar 

  • Carboni E, Spielewoy C, Vacca C, Nosten-Bertrand M, Giros B, Di Chiara G (2001) Cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens of mice lacking the dopamine transporter gene. J Neurosci 21(RC141):1–4

    PubMed  Google Scholar 

  • Chen JP, Paredes W, Li J, Smith D, Lowinson J, Gardner EL (1990) Delta 9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis. Psychopharmacology 102:156–162

    Article  PubMed  CAS  Google Scholar 

  • Fantegrossi WE, Ullrich T, Rice KC, Woods JH, Winger G (2002) 3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) and its stereoisomers as reinforcers in rhesus monkeys: serotoninergic involvement. Psychopharmacology 161:356–364

    Article  PubMed  CAS  Google Scholar 

  • Gouzoulis-Mayfrank E, Daumann J (2006) The confounding problem of polydrug use in recreational ecstasy/MDMA users: a brief overview. J Psychopharmacol 20:188–193

    Article  PubMed  CAS  Google Scholar 

  • Justinova Z, Tanda G, Redhi GH, Goldberg SR (2003) Self-administration of delta9-tetrahydrocannabinol (THC) by drug naive squirrel monkeys. Psychopharmacology (Berl) 169:135–140

    Article  CAS  Google Scholar 

  • Kankaanpää A, Meririnne E, Lillsunde P, Seppala 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 

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

    Article  PubMed  CAS  Google Scholar 

  • Lepore M, Vorel SR Lowinson J, Gardner EL (1995) Conditioned place preference induced by delta 9-tetrahydrocannabinol: comparison with cocaine, morphine, and food reward. Life Sci 56:2073–2080

    Article  PubMed  CAS  Google Scholar 

  • Malone DT, Taylor DA (1999) Modulation by fluoxetine of striatal dopamine release following Delta9-tetrahydrocannabinol: a microdialysis study in conscious rats. Br J Pharmacol 128:21–26

    Article  PubMed  CAS  Google Scholar 

  • Marona-Lewicka D, Rhee GS, Sprague JE, Nichols DE (1996) Reinforcing effects of certain serotonin-releasing amphetamine derivatives. Pharmacol Biochem Behav 53:99–105

    Article  PubMed  CAS  Google Scholar 

  • Morley KC, Li KM, Hunt GE, Mallet PE, McGregor IS (2004) Cannabinoids prevent the acute hyperthermia and partially protect against the 5-HT depleting effects of MDMA (“Ecstasy”) in rats. Neuropharmacology 46:954–965

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Franklin KBJ (1997) The mouse brain in stereotaxic coordinates. Academic, San Diego

    Google Scholar 

  • Ratzenboeck E, Saria A, Kriechbaum N, Zernig G (2001) Reinforcing effects of MDMA (“ecstasy”) in drug-naive and cocaine-trained rats. Pharmacology 62:138–144

    Article  PubMed  CAS  Google Scholar 

  • Robledo P, Balerio G, Berrendero F, Maldonado R (2004a) Study of the behavioural responses related to the potential addictive properties of MDMA in mice. Naunyn Schmiedebergs Arch Pharmacol 369:338–349

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  • Salzmann J, Marie-Claire C, Le Guen S, Roques BP, Noble F (2003) Importance of ERK activation in behavioural and biochemical effects induced by MDMA in mice. Br J Pharmacol 140:831–838

    Article  PubMed  CAS  Google Scholar 

  • Schenk S, Gittings D, Johnstone M, Daniela E (2003) Development, maintenance and temporal pattern of self-administration maintained by ecstasy (MDMA) in rats. Psychopharmacology 169:21–27

    Article  PubMed  CAS  Google Scholar 

  • Soria G, Mendizabal V, Tourino C, Robledo P, Ledent C, Parmentier M, Maldonado R, Valverde O (2005) Lack of CB1 cannabinoid receptor impairs cocaine self-administration. Neuropsychopharmacology 30:1670–1680

    Article  PubMed  CAS  Google Scholar 

  • Tanda G, Pontieri FE, Di Chiara G (1997) Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science 276:2048–2050

    Article  PubMed  CAS  Google Scholar 

  • Tossmann P, Boldt S, Tensil MD (2001) The use of drugs within the techno party scene in European metropolitan cities. Eur Addict Res 7:2–23

    Article  PubMed  CAS  Google Scholar 

  • Trigo JM, Panayi F, Soria G, Maldonado R, Robledo P (2006) A reliable model of intravenous MDMA self-administration in naive mice. Psychopharmacology 184:212–220

    Article  PubMed  CAS  Google Scholar 

  • Trigo JM, Renoir T, Lanfumey L, Hamon M, Lesch KP, Robledo P, Maldonado R (2007) MDMA self-administration is abolished in serotonin transporter knock-out mice. Biological Psychiatry (in press)

  • Valjent E, Maldonado R (2000) A behavioural model to reveal place preference to delta 9-tetrahydrocannabinol in mice. Psychopharmacology 147:436–438

    Article  PubMed  CAS  Google Scholar 

  • Valjent E, Mitchell JM, Besson MJ, Caboche J, Maldonado R (2002) Behavioural and biochemical evidence for interactions between Delta 9-tetrahydrocannabinol and nicotine. Br J Pharmacol 135:564–578

    Article  PubMed  CAS  Google Scholar 

  • White SR, Obradovic T, Imel KM, Wheaton MJ (1996) The effects of methylenedioxymethamphetamine (MDMA, “Ecstasy”) on monoaminergic neurotransmission in the central nervous system. Prog Neurobiol 49:455–479

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto BK, Spanos LJ (1988) The acute effects of methylenedioxymethamphetamine on dopamine release in the awake-behaving rat. Eur J Pharmacol 148:195–203

    Article  PubMed  CAS  Google Scholar 

  • Zimmermann P, Wittchen HU, Waszak F, Nocon A, Hofler M, Lieb R (2005) Pathways into ecstasy use: the role of prior cannabis use and ecstasy availability. Drug Alcohol Depend 79:331–341

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Ms. Dulce Real Muñoz for her expert help in the microdialysis experiments, and Mr. Jordi Ortuño for his assistance with the HPLC methodology. This work was supported by FIS grant number 03/0305, Plan Nacional Sobre Drogas 2005, NIH-NIDA (USA), Extra-mural research project (#5 R01 DA016768), I.S. CARLOS III Redes de grupos ISCIII (# RTA G03/005), Ministerio de Ciencia y Tecnología (# BFU2004–00920/BFI and # GEN2003–20651), Generalitat de Catalunya 2005SGR00131 and GENADDICT LSHM-CT-2004–05166.

Author information

Authors and Affiliations

  1. Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain

    Patricia Robledo, Jose M. Trigo, Fany Panayi & Rafael Maldonado

  2. Institut Municipal d’Investigació Mèdica (IMIM), Barcelona, Spain

    Patricia Robledo & Rafael de la Torre

  3. Universitat Pompeu Fabra, Calle Dr. Aiguader, 88, 08003, Barcelona, Spain

    Patricia Robledo

Authors
  1. Patricia Robledo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jose M. Trigo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fany Panayi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rafael de la Torre
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rafael Maldonado
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patricia Robledo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Robledo, P., Trigo, J.M., Panayi, F. et al. Behavioural and neurochemical effects of combined MDMA and THC administration in mice. Psychopharmacology 195, 255–264 (2007). https://doi.org/10.1007/s00213-007-0879-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-007-0879-8

Keywords

Search

Navigation