Abstract
Although the rewarding effects of 3,4-methylenedioxy-metamphetamine (MDMA) have been demonstrated in self-administration and conditioned place preference (CPP) procedures, its addictive potential (ie, the vulnerability to relapse, measured by its ability to induce reinstatement of an extinguished response), remains poorly understood. In this study, the effects of MDMA (5, 10, and 20 mg/kg) on the acquisition, extinction and reinstatement of CPP were evaluated in mice, using two different protocols during acquisition of CPP. In the first experiment, animals were trained using a two-session/day schedule (MDMA and saline for 4 consecutive days), whereas in the second experiment, they were trained using an alternating day schedule (MDMA and saline each 48 h). After extinction, the ability of drug priming to reinstate CPP was evaluated. In Experiment 1, MDMA did not significantly increase the time spent in the drug-paired compartment during the post-conditioning (Post-C) test, although the preference was evident a week afterwards, lasting between 2 and 21 weeks. No reinstatement was observed after MDMA priming. In Experiment 2, all doses produced CPP in Post-C, which lasted between 1 and 4 weeks. MDMA induces reinstatement at doses up to 4 times lower than those used in conditioning. The analyses of brain monoamines revealed that the daily schedule of treatment induces a non-dose-dependent decrease in dopamine and serotonin (5-HT) in the striatum, whereas the alternating schedule produces a dose-dependent decrease of 5-HT in the cortex. These results demonstrate that MDMA produces long-lasting rewarding effects and reinstatement after extinction, suggesting the susceptibility of this drug to induce addiction.
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References
Acquas E, Marrocu P, Pisanu A, Cadoni C, Zernig G, Saria A et al (2001). Intravenous administration of ecstasy (3,4-methylenedioxymethamphetamine) enhances cortical and striatal acetylcholine release in vivo. Eur J Pharmacol 418: 207–211.
Beardsley PM, Balster RL, Harris LS (1986). Self-administration of methylenedioxymethamphetamine (MDMA) by rhesus monkeys. Drug Alcohol Depend 18: 149–157.
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.
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.
Bilsky EJ, Hubell CL, Delconte JD, Reid LD (1991). MDMA produces a conditioned place preference and elicits ejaculation in male rats: a modulatory role for the endogenous opioids. Pharmacol Biochem Behav 40: 443–447.
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.
Boot BP, Mechan AO, McCann UD, Ricaurte GA (2002). MDMA- and p-chlorophenylalanine-induced reduction in 5-HT concentrations: effects on serotonin transporter densities. Eur J Pharmacol 453: 239–244.
Braida D, Sala M (2002). Role of the endocannabinoid system in MDMA intracerebral self-administration in rats. Br J Pharmacol 136: 1089–1092.
Braida D, Iosuè S, Pegorini S, Sala M (2005). 3,4 Methylenedioxymethamphetamine-induced conditioned place preference (CPP) is mediated by the endocannabinoid system. Pharmacol Res 51: 177–182.
Cadoni C, Solinas M, Pisanu A, Zernig G, Acquas E, Di Chiara G (2005). Effects of 3,4-methylendioxymethamphetamine (MDMA, ‘ecstasy’) on dopamine transmission in the nucleus accumbens shell and core. Brain Res 1055: 143–148.
Camarero J, Sanchez V, O’Shea E, Green AR, Colado MI (2002). Studies, using in vivo microdialysis, on the effect of the dopamine uptake inhibitor GBR 12909 on 3,4-methylenedioxymethamphetamine (‘ecstasy’)-induced dopamine release and free radical formation in the mouse striatum. J Neurochem 81: 961–972.
Carroll ME, Comer SD (1996). Animal models of relapse. Exp Clin Psychopharmacol 4: 11–18.
Colado MI, Camarero J, Mechan AO, Sanchez V, Esteban B, Elliott JM et al (2001). A study of the mechanisms involved in the neurotoxic action of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) on dopamine neurons in mouse brain. Br J Pharmacol 134: 1711–1723.
Colado MI, O’Shea E, Green AR (2004). Acute and long-term effects of MDMA on cerebral dopamine biochemistry and function. Psychopharmacology 173: 249–263.
Cole JC, Sumnall HR (2003). The pre-clinical behavioural pharmacology of 3,4-methylenedioxymethamphetamine (MDMA). Neurosci Biobehav Rev 27: 199–217.
Cole JC, Sumnall HR, O’Shea E, Marsden CA (2003). Effects of MDMA exposure on the conditioned place preference produced by other drugs of abuse. Psychopharmacology 166: 383–390.
Cornish JL, Shahnawaz Z, Thompson MR, Wong S, Morley KC, Hunt GE et al (2003). Heat increases 3,4-methylenedioxymethamphetamine self-administration and social effects in rats. Eur J Pharmacol 482: 339–341.
Childress AR, Mozley PD, McElgin W, Fitzgerald J, Reivich M, ÓBrien CP (1999). Limbic activation during cue-induced cocaine craving. Am J Psychiatry 156: 11–18.
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.
Escobedo I, O’Shea E, Orio L, Sanchez V, Segura M, de la Torre R et al (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.
Fantegrossi WE, Ullrich T, Rice KC, Woods JH, Winger G (2002). 3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy’) and its stereoisomers as reinforcers in rhesus monkeys: serotonergic involvement. Psychopharmacology 161: 356–364.
Fantegrossi WE, Woolverton WL, Kilbourn M, Sherman P, Yuan J, Hatzidimitriou G et al (2004). Behavioral and neurochemical consequences of long-term intravenous self-administration of MDMA and its enantiomers by rhesus monkeys. Neuropsychopharmacology 29: 1270–1281.
Gough B, Ali SF, Slikker W, Holson RR (1991). Acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on monoamines in rat caudate. Pharmacol Biochem Behav 39: 619–623.
Grimm JW, Hope BT, Wise RA, Shaham Y (2001). Incubation of cocaine craving after withdrawal. Nature 412: 141–142.
Herzig V, Capuani EM, Kovar KA, Schmidt WJ (2005). Effects of MPEP on expression of food-, MDMA- or amphetamine-conditioned place preference in rats. Addict Biol 10: 243–249.
Hiramatsu M, Cho AK (1990). Enantiomeric differences in the effects of 3,4-methylenedioxymethamphetamine on extracellular monoamines and metabolites in the striatum of freely-moving rats: an in vivo microdialysis study. Neuropharmacology 29: 269–275.
Kankaanpaa 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.
Koch S, Galloway MP (1997). MDMA induced dopamine release in vivo: role of endogenous serotonin. J Neural Transm 104: 135–146.
Lamb R, Griffiths R (1987). Self-injections of d-3,4-methylenedioxymethamphetamine (MDMA) in the baboon. Psychopharmacology 91: 268–272.
Li S-M, Ren Y-H, Zheng J-W (2002). Effect of 7-nitroindazole on drug-priming reinstatement of D-methamphetamine-induced conditioned place preference. Eur J Pharmacol 443: 205–206.
Lile JA, Ross JT, Nader MA (2005). A comparison of the reinforcing efficacy of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) with cocaine in rhesus monkeys. Drug Alcohol Depend 78: 135–140.
Lu L, Grimm JW, Dempsey J, Shaham Y (2004). Cocaine seeking over extended withdrawal periods in rats: different time courses of responding induced by cocaine cues versus cocaine priming over the first 6 months. Psychopharmacology 176: 101–108.
Maldonado C, Rodriguez-Arias M, Castillo A, Aguilar MA, Miñarro J (2006). Gamma-hydroxybutyric acid affects the acquisition and reinstatement of cocaine-induced conditioned place preference in mice. Behav Pharmacol 17: 119–131.
Manzanedo C, Aguilar MA, Rodríguez-Arias M, Miñarro J (2001). Effects of dopamine antagonists with different receptor blockade profiles on morphine-induced place preference in male mice. Behav Brain Res 121: 189–197.
Marona-Lewicka D, Rhee G-S, Sprague JE, Nichols DE (1996). Reinforcing effects of certain serotonin-releasing amphetamine derivatives. Pharmacol Biochem Behav 53: 99–105.
McGregor IS, Clemens KJ, van der Plass G, Li KM, Hunt GE, Chen F et al (2003). Increased anxiety 3 months after brief exposure to MDMA (‘ecstasy’) in rats: association with altered 5-HT transporter and receptor density. Neuropsychopharmacology 28: 1472–1484.
Meyer A, Mayerhofer A, Kovar K-A, Schmidt WJ (2002). Rewarding effects of the optical isomers of 3,4-methylenedioxy-methylamphetamine (‘Ecstasy’) and 3,4-methylenedioxy-ethylamphetamine (‘Eve’) measured by conditioned place preference in rats. Neurosci Lett 330: 280–284.
Modi GM, Yang PB, Swann AC, Dafny N (2006). Chronic exposure to MDMA (Ecstasy) elicits behavioral sensitization in rats but fails to induce cross-sensitization to other psychostimulants. Behav Brain Funct 2: 1.
Nair SG, Gudelsky GA (2006). 3,4-Methylenedioxymethamphetamine enhances the release of acetylcholine in the prefrontal cortex and dorsal hippocampus of the rat. Psychopharmacology 184: 182–189.
Nichols DE (1986). Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: entactogens. J Psychoactive Drugs 18: 305–313.
O’Brien CP (1997). A range of research-based pharmacotherapies for addiction. Science 278: 66–70.
O’Shea E, Escobedo J, Orio L, Sanchez V, Navarro M, Green AR et al (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.
Reveron ME, Monks TJ, Duvauchelle CL (2005). Age-dependent (+)MDMA-mediated neurotoxicity in mice. Neurotoxicology 26: 1031–1040.
Ribeiro Do Couto B, Aguilar MA, Rodriguez-Arias M, Miñarro J (2005a). Long-lasting rewarding effects of morphine induced by drug primings. Brain Res 1050: 53–63.
Ribeiro Do Couto B, Aguilar MA, Manzanedo C, Rodriguez-Arias M, Miñarro J (2005b). NMDA glutamate but not dopamine antagonists blocks drug-induced reinstatement of morphine place preference. Brain Res Bull 64: 493–503.
Ribeiro Do Couto B, Aguilar MA, Manzanedo C, Rodriguez-Arias M, Armario A, Min¯arro J (2006). Social stress is as effective as physical stress in reinstating morphine-induced place preference in mice. Psychopharmacology 185: 459–470.
Ricaurte G, Bryan G, Strauss L, Seiden L, Schuster C (1985). Hallucinogenic amphetamine selectively destroys brain serotonin nerve terminals. Science 229: 986–988.
Robledo P, Balerio B, Berrendero F, Maldonado R (2004a). Study of the behavioural responses related to the potential addictive properties of MDMA in mice. Naunyn-Schmiedeberg's Arch Pharmacol 369: 338–349.
Robledo P, Mendizabal V, Ortuño J, de la Torre R, Kieffer BL, Maldonado R (2004b). The rewarding properties of MDMA are preserved in mice lacking m-opioid receptors. Eur J Neurosci 20: 853–858.
Salzmann J, Marie-claire C, Le Guen S, Roques BP, Noble F (2003). Importance of ERK activation in behavioral and biochemical effects induced by MDMA in mice. Br J Pharmacol 140: 831–838.
Schechter MD (1991). Effect of MDMA neurotoxicity upon its conditioned place preference and discrimination. Pharmacol Biochem Behav 38: 539–544.
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.
Schmidt CJ, Levin JA, Lovenberg W (1987). In vitro and in vivo neurochemical effects of methylenedioxymethamphetamine on striatal monoaminergic systems in the rat brain. Biochem Pharmacol 36: 747–755.
Shaham Y, Shalev U, Lu L, de Wit H, Stewart J (2003). The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168: 3–20.
Shalev U, Grimm JW, Shaham Y (2002). Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54: 1–42.
Stone DM, Johnson M, Hanson GR, Gibb JW (1987). A comparison of the neurotoxic potential of methylenedioxyamphetamine (MDA) and its N-methylated and N-ethylated derivatives. Eur J Pharmacol 134: 245–248.
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.
Weiss F (2005). Neurobiology of craving, conditioned reward and relapse. Current Opinion Pharmacol 5: 9–19.
White SR, Duffy P, Kalivas PW (1994). Methylenedioxymethamphetamine depresses glutamate-evoked neuronal firing and increases extracellular levels of dopamine and serotonin in the nucleus accumbens in vivo. Neuroscience 62: 41–50.
Yamamoto BK, Spanos LJ (1988). The acute effects of methylenedioxy-methamphetamine on dopamine release in the awake-behaving rat. Eur J Pharmacol 148: 195–203.
Acknowledgements
This work was supported by the following grants:
Ministerio de Sanidad y Consumo, Instituto de Salud ‘Carlos III’ (FIS), Redes Temáticas de Investigación Cooperativa (G03/005) and Proyectos de Investigación (PI052165). Ministerio de Educación y Ciencia, Dirección General de Investigación and FEDER (SEJ2005-00316/PSIC) (Spain). Conselleria de Sanitat, Agencia Valenciana de Salud. Dirección General de Drogodependencias (FEPAD) and Conselleria d’ empresa, Universitat i Ciencia, Proyectos I+D (GV04B46, GV06/355, ACOMP06/211), Generalitat Valenciana (Spain). Bruno Ribeiro Do Couto was supported by grant SFRH/BD/4559/2001 of the Fundação Para a Ciência e a Tecnologia, Ministério da Ciência e da Tecnologia (Portugal).
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Daza-Losada, M., Ribeiro Do Couto, B., Manzanedo, C. et al. Rewarding Effects and Reinstatement of MDMA-Induced CPP in Adolescent Mice. Neuropsychopharmacol 32, 1750–1759 (2007). https://doi.org/10.1038/sj.npp.1301309
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DOI: https://doi.org/10.1038/sj.npp.1301309
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