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MDMA attenuates THC withdrawal syndrome in mice

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Abstract

Introduction

3, 4-Methylenedioxymethamphetamine (MDMA) and cannabis are widely abused illicit drugs that are frequently consumed in combination. Interactions between these two drugs have been reported in several pharmacological responses observed in animals, such as body temperature, anxiety, cognition, and reward. However, the interaction between MDMA and cannabis in addictive processes such as physical dependence has not been elucidated yet.

Discussion

In this study, the effects of acute and chronic MDMA were evaluated on the behavioral manifestations of Δ9-tetrahydrocannabinol (THC) abstinence in mice. THC withdrawal syndrome was precipitated by injecting the cannabinoid antagonist rimonabant (10 mg/kg, i.p.) in mice chronically treated with THC and receiving MDMA (2.5, 5 and 10 mg/kg i.p.) or saline just before the withdrawal induction or chronically after the THC administration.

Results

Both chronic and acute MDMA decreased in a dose-dependent manner the severity of THC withdrawal. In vivo microdialysis experiments showed that acute MDMA (5 mg/kg, i.p.) administration increased extracellular serotonin levels in the prefrontal cortex, but not dopamine levels in the nucleus accumbens. Our results also indicate that the attenuation of THC abstinence symptoms was not due to a direct interaction between rimonabant and MDMA nor to the result of the locomotor stimulating effects of MDMA.

Conclusion

The modulation of the cannabinoid withdrawal syndrome by acute or chronic MDMA suggests a possible mechanism to explain the associated consumption of these two drugs in humans.

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Abbreviations

THC:

Δ9-tetrahydrocannabinol

DA:

dopamine

5-HT:

serotonin

NE:

norepinephrine

MDMA:

3, 4-methylenedioxymethamphetamine

References

  • Aceto MD, Scates SM, Lowe JA, Martin BR (1996) Dependence on delta 9-tetrahydrocannabinol: studies on precipitated and abrupt withdrawal. J Pharmacol Exp Ther 278:1290–1295

    PubMed  CAS  Google Scholar 

  • Ameri A (1999) The effects of cannabinoids on the brain. Prog Neurobiol 58:315–348

    Article  PubMed  CAS  Google Scholar 

  • Beardsley PM, Balster RL, Harris LS (1986) Self-administration of methylenedioxymethamphetamine (MDMA) by rhesus monkeys. Drug Alcohol Depend 18:149–157

    Article  PubMed  CAS  Google Scholar 

  • Bilsky EJ, Hui YZ, 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 Parmacol 136:1089–1092

    Article  CAS  Google Scholar 

  • Cheer JF, Cadogan AK, Marsden CA, Fone KC, Kendall DA (1999) Modification of 5-HT2 receptor mediated behaviour in the rat by oleamide and the role of cannabinoid receptors. Neuropharmacology 38:533–541

    Article  PubMed  CAS  Google Scholar 

  • Climko RP, Roehrich H, Sweeney DR, Al Razi J (1986) Ecstacy: a review of MDMA and MDA. Int J Psychiatry Med 16:359–372

    Article  PubMed  Google Scholar 

  • Colado MI, Murray TK, Green AR (1993) 5-HT loss in rat brain following 3,4-methylenedioxymethamphetamine (MDMA), p-chloroamphetamine and fenfluramine administration and effects of chlormethiazole and dizocilpine. Br J Pharmacol 108:583–589

    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 

  • 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  PubMed  CAS  Google Scholar 

  • Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA 87:1932–1936

    Article  PubMed  CAS  Google Scholar 

  • Hutcheson DM, Tzavara ET, Smadja C, Valjent E, Roques BP, Hanoune J, Maldonado R (1998) Behavioural and biochemical evidence for signs of abstinence in mice chronically treated with delta-9-tetrahydrocannabinol. Br J Pharmacol 125:1567–1577

    Article  PubMed  CAS  Google Scholar 

  • Iravani MM, Jackson MJ, Kuoppamaki M, Smith LA, Jenner P (2003) 3,4-methylenedioxymethamphetamine (ecstasy) inhibits dyskinesia expression and normalizes motor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates. J Neurosci 23:9107–9115

    PubMed  CAS  Google Scholar 

  • Johnson MP, Hoffman AJ, Nichols DE (1986) Effects of the enantiomers of MDA, MDMA and related analogues on [3H]serotonin and [3H]dopamine release from superfused rat brain slices. Eur J Pharmacol 132:269–276

    Article  PubMed  CAS  Google Scholar 

  • Justinova Z, Solinas M, Tanda G, Redhi GH, Goldberg SR (2005) The endogenous cannabinoid anandamide and its synthetic analog R(+)-methanandamide are intravenously self-administered by squirrel monkeys. J Neurosci 25:5645–5650

    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 

  • Lesscher HM, Hoogveld E, Burbach JP, van Ree JM, Gerrits MA (2005) Endogenous cannabinoids are not involved in cocaine reinforcement and development of cocaine-induced behavioural sensitization. Eur Neuropsychopharmacol 15:31–37

    Article  PubMed  CAS  Google Scholar 

  • Lichtman AH, Martin BR (2002) Marijuana withdrawal syndrome in the animal model. J Clin Pharmacol 42:20S–27S

    PubMed  CAS  Google Scholar 

  • Maldonado R (2002) Study of cannabinoid dependence in animals. Pharmacol Ther 95:153–164

    Article  PubMed  CAS  Google Scholar 

  • Maldonado R, Rodriguez de Fonseca F (2002) Cannabinoid addiction: behavioral models and neural correlates. J Neurosci 22:3326–3331

    PubMed  CAS  Google Scholar 

  • Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564

    Article  PubMed  CAS  Google Scholar 

  • Mechoulam R, Shani A, Edery H, Grunfeld Y (1970) Chemical basis of hashish activity. Science 169:611–612

    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 

  • Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Franklin KBJ (1997) The Mouse Brain in Stereotaxic Coordinates, vol 1. Academic, San Diego, pp 268–272

    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  PubMed  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  PubMed  Google Scholar 

  • Rodriguez de Fonseca F, Carrera MR, Navarro M, Koob GF, Weiss F (1997) Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal. Science 276:2050–2054

    Article  PubMed  CAS  Google Scholar 

  • Rubino T, Vigano D, Massi P, Parolaro D (2000) Changes in the cannabinoid receptor binding, G protein coupling, and cyclic AMP cascade in the CNS of rats tolerant to and dependent on the synthetic cannabinoid compound CP55,940. J Neurochem 75:2080–2086

    Article  PubMed  CAS  Google Scholar 

  • Smart RG, Ogborne AC (2000) Drug use and drinking among students in 36 countries. Addict Behav 25:455–460

    Article  PubMed  CAS  Google Scholar 

  • Steiner H, Bonner TI, Zimmer AM, Kitai ST, Zimmer A (1999) Altered gene expression in striatal projection neurons in CB1 cannabinoid receptor knockout mice. Proc Natl Acad Sci USA 96:5786–5790

    Article  PubMed  CAS  Google Scholar 

  • Tanda G, Loddo P, Di Chiara G (1999) Dependence of mesolimbic dopamine transmission on delta9-tetrahydrocannabinol. Eur J Pharmacol 376:23–26

    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 (Berl) 184:212–220

    Article  CAS  Google Scholar 

  • Tzavara ET, Davis RJ, Perry KW, Li X, Salhoff C, Bymaster FP, Witkin JM, Nomikos GG (2003) The CB1 receptor antagonist SR141716A selectively increases monoaminergic neurotransmission in the medial prefrontal cortex: implications for therapeutic actions. Br J Pharmacol 138:544–553

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Valverde O, Maldonado R, Valjent E, Zimmer AM, Zimmer A (2000) Cannabinoid withdrawal syndrome is reduced in pre-proenkephalin knock-out mice. J Neurosci 20:9284–9289

    PubMed  CAS  Google Scholar 

  • Winstock AR, Griffiths P, Stewart D (2001) Drugs and the dance music scene: a survey of current drug use patterns among a sample of dance music enthusiasts in the UK. Drug Alcohol Depend 64:9–17

    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 

  • Young JM, McGregor IS, Mallet PE (2005) Co-administration of THC and MDMA (‘ecstasy’) synergistically disrupts memory in rats. Neuropsychopharmacology 30:1475–1482

    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 

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Acknowledgement

This study was supported by grants from Spanish MCYT (SAF 2004/568; BFU 2004/920BFI), Generalitat de Catalunya (2005SGR00131), European Communities (GENADDICT LSHM-CT-2004-005166), and National Institute of Health (NIH) (extramural research project #DA016768). CT has a fellowship supported by the Department of Education and Universities from Generalitat de Catalunya and by the Social European Fund. Ms Dulce Real in this work is kindly acknowledged for her excellent technical assistance in the in vivo microdialysis experiments.

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Authors and Affiliations

  1. Grup de Recerca de Neurobiologia del Comportament, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, C/ Dr. Aiguader 80, 08003, Barcelona, Spain

    Clara Touriño & Olga Valverde

  2. Laboratori de Neurofarmacologia, Departament de Ciències de Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, C/ Dr Aiguader 80, 08003, Barcelona, Spain

    Rafael Maldonado

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  1. Clara Touriño
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  2. Rafael Maldonado
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  3. Olga Valverde
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Correspondence to Olga Valverde.

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Touriño, C., Maldonado, R. & Valverde, O. MDMA attenuates THC withdrawal syndrome in mice. Psychopharmacology 193, 75–84 (2007). https://doi.org/10.1007/s00213-007-0772-5

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  • DOI: https://doi.org/10.1007/s00213-007-0772-5

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