Skip to main content

Advertisement

SpringerLink
Log in

Development, maintenance and temporal pattern of self-administration maintained by ecstasy (MDMA) in rats

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

Abstract

Rationale

±3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") use is increasing around the globe but there is a paucity of studies examining the abuse liability of this drug.

Objectives

The ability of drugs to reinforce operant responding in laboratory animals is a valid and reliable predictor of abuse potential. MDMA is self-administered by humans, but there have been few reports of reliable self-administration by drug-naive laboratory animals. The present study sought to examine the acquisition and maintenance of MDMA self-administration by laboratory rats. The influence of prior training with cocaine self-administration on the acquisition of MDMA self-administration was also examined.

Methods

MDMA self-administration (0.25–2.0 mg/kg per infusion) was examined in rats that were first trained to self-administer cocaine as well as by those that were drug-naive. The dose-dependency of MDMA self-administration and the temporal pattern of responding maintained by various doses of MDMA were examined. In some rats, self-administration of MDMA during a 24-h session was also examined.

Results

MDMA was self-administered by laboratory rats that were experienced with self-administration of cocaine as well as by rats that were initially drug naive. For drug naive rats, the acquisition of MDMA self-administration (1.0 mg/kg per infusion) developed gradually during daily test sessions. The latency to acquisition of self-administration was shorter in cocaine-trained rats. Self-administration was dose-dependent, extinguished when saline was substituted for MDMA and, was reinstated when MDMA was reintroduced. During a 24-h self-administration session, a high rate of responding was produced during the first hour of the test session followed by a steady and lower rate of two to four responses per hour during subsequent hours of the test.

Conclusions

These results suggest that prior experience with cocaine self-administration facilitates the acquisition of MDMA self-administration. The results also suggest that MDMA has abuse liability and that increased use of the drug should raise concern of a growing and widespread potential for chronic abuse.

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

  • Baker LE, Broadbent J, Michael EK, Matthews PK, Metosh CA, Saunders RB, West WB, Appel JB (1995) Assessment of the discriminative stimulus effects of the optical isomers of ecstasy (3,4-methylenedioxymethamphetamine; MDMA). Behav Pharmacol 6:263–275

    CAS  PubMed  Google Scholar 

  • Bankson MG, Cunningham KA (2001) 3,4-Methylenedioxymethamphetamine (MDMA) as a unique model of serotonin receptor function and serotonin-dopamine interactions. J Pharmacol Exp Ther 297:846–852

    CAS  PubMed  Google Scholar 

  • Bankson MG, Cunningham KA (2002) Pharmacological studies of the acute effects of (+)-3,4-methylenedioxymethamphetamine on locomotor activity: role of 5-HT1B/1D and 5-HT2 receptors. Neuropsychopharmacology 26:40–52

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Callaway CW, Geyer MA (1992) Tolerance and cross-tolerance to the activating effects of 3,4-methylenedioxymethamphetamine and a 5-hydroxytryptamine1B agonist. J Pharmacol Exp Ther 263:318–326

    CAS  PubMed  Google Scholar 

  • Callaway CW, Wing L, Geyer MA (1990) Serotonin release contributes to the stimulant effects of 3,4-methylenedioxymethamphetamine in rats. J Pharmacol Exp Ther 254:456–464

    CAS  PubMed  Google Scholar 

  • Carroll ME, Lac ST (1997) Acquisition of IV amphetamine and cocaine self-administration in rats as a function of dose. Psychopharmacology 129:206–214

    Article  CAS  PubMed  Google Scholar 

  • De Deurwaerdere P, L'hirondel M, Bonhomme N, Lucas G, Cheramy A, Spaminato U (1997) Serotonin stimulation of 5-HT4 receptors indirectly enhances in vivo dopamine release in the rat. J Neurochem 68:195–203

    PubMed  Google Scholar 

  • Deneau G, Yanaghita T, Seevers MH (1969) Self-administration of psychoactive substances by the monkey. Psychopharmacologia 16:30–48

    CAS  PubMed  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: serotonergic involvement. Psychopharmacology 161:356–364

    Google Scholar 

  • Fischman MW, Schuster CR (1978) Drug seeking: a behavioral analysis in animals and humans. NIDA Res Monogr 20:4–23

    CAS  PubMed  Google Scholar 

  • Fletcher PJ, Robinson SR, Slippoy DL (2001) Pre-exposure to (±)3,4-methylenedioxymethamphetamine (MDMA) facilitates acquisition of intravenous cocaine self-administration in rats. Neuropsychopharmacology 25:195–203

    Article  CAS  PubMed  Google Scholar 

  • Gudelsky GA, Yamamoto BK, Nash (1994) Potentiation of 3,4-methylenedioxymethamphetamine-induced dopamine release and serotonin neurotoxicity by 5-HT2 receptor agonists. Eur J Pharmacol 264:325–330

    Article  CAS  PubMed  Google Scholar 

  • Hansen JP, Riddle EL, Sandoval V, Brown JM, Gibb JW, Hanson GR, Fleckenstein AE (2002) Methylenedioxymethamphetamine decreases plasmalemmal and vesicular dopamine transport: mechanisms and implications for neurotoxicity. J Pharmacol Exp Ther 300:1093–1100

    Google Scholar 

  • Hekmatpanah CR, Peroutka SJ (1990) 5-Hydroxytryptamine uptake blockers attenuate the 5-hydroxytryptamine-releasing effect of 3,4-methyenedioxymethamphetamine and related agents. Eur J Pharmacol 177:95–98

    Article  CAS  PubMed  Google Scholar 

  • Hernandez-Lopez C, Farre M, Roset PN, Menoyo E, Pizarro N, Ortuno J, Torrens M, Cami J, de La Torre R (2002) 3,4-Methylenedioxymethamphetamine (ecstasy) and alcohol interactions in humans: psychomotor performance, subjective effects, and pharmacokinetics. J Pharmacol Exp Ther 300:236–244

    Google Scholar 

  • Herve D, Pickel VM, Joh TH, Beaudet A (1987) Serotonin axon terminals in the ventral tegmental area of the rat: fine structure and synaptic input to dopaminergic terminals. Brain Res 435:71–83

    CAS  PubMed  Google Scholar 

  • Horan B, Gardner EL, Ashby CR Jr (2000) Enhancement of conditioned place preference response to cocaine in rats following subchronic administration of 3,4-methylenedioxymethamphetamine (MDMA). Synapse 35:160–162

    Article  CAS  PubMed  Google Scholar 

  • Howell LL, Wilcox KM (2001) The dopamine transporter and cocaine medication development: drug self-administration in nonhuman primates. J Pharmacol Exp Ther 298:1–6

    PubMed  Google Scholar 

  • Iravani MM, Asari D, Patel J, Wieczorek WJ, Kruk ZL (2000) Direct effects of 3,4-methylenedioxymethamphetamine (MDMA) on serotonin or dopamine release and uptake in the caudate putamen, nucleus accumbens, substantia nigra pars reticulata, and the dorsal raphe nucleus slices. Synapse 36:275–285

    Article  CAS  PubMed  Google Scholar 

  • Kalant H (2001) The pharmacology and toxicology of "ecstasy" (MDMA) and related drugs. CMAJ 165:917–928

    CAS  PubMed  Google Scholar 

  • Kalivas PW, Stewart J (1991) Dopamine transmission in the initiation and expression of drug- and stress-induced sensitisation to motor activity. Brain Res Rev 16:223–244

    CAS  PubMed  Google Scholar 

  • Kalivas PW, Duffy P, White SR (1998) MDMA elicits behavioral and neurochemical sensitization in rats. Neuropsychopharmacology 18:469–479

    Google Scholar 

  • Kuhar MJ, Ritz M, Boja JW (1991) The dopamine hypothesis of the reinforcing properties of cocaine. Trends Neurosci 14:299–302

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Liechti ME, Vollenweider FX (2000) Acute psychological and physiological effects of MDMA ("Ecstasy") after haloperidol pretreatment in healthy humans. Eur Neuropsychopharmacol 10:289–295

    CAS  PubMed  Google Scholar 

  • Liechti ME, Vollenweider FX (2001) Which neuroreceptors mediate the subjective effects of MDMA in humans? A summary of mechanistic studies. Hum Psychopharmacol Clin Exp 16:589–598

    Google Scholar 

  • Marona-Lewicka D, Rhee GS, Sprague JE, Nichols DE (1991) MDL72222, a serotonin 5-HT3 receptor antagonist, blocks MDMA's ability to establish a conditioned place preference. Pharmacol Biochem Behav 39:509–512

    PubMed  Google Scholar 

  • Mayerhoffer A, Kovar K-A, Schmidt WJ (2001) Changes in serotonin, dopamine and noradrenaline levels in striatum and nucleus accumbens after repeated administration of the abused drug MDMA in rats. Neurosci Lett 308:99–102

    Article  PubMed  Google Scholar 

  • McCreary AC, Bankson MG, Cunningham KA (1999) Pharmacological studies of the acute and chronic effects of (+)-3,4-methyenedioxymethamphetamine on locomotor activity: role of the 5-hydroxytryptamine1A and 5-hydroxytryptamine1B/1D receptors. J Pharmacol Exp Ther 290:965–973

    CAS  PubMed  Google Scholar 

  • Mello NK, Negus SS (1996) Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures. Neuropsychopharmacology 14:375–424

    PubMed  Google Scholar 

  • Metzger RR, Hanson GR, Gibb JW, Fleckenstein AE (1998) 3,4-Methylenedioxymethamphetamine-induced acute changes in dopamine transporter function. Eur J Pharmacol 349:205–210

    Article  CAS  PubMed  Google Scholar 

  • Nash JF, Brodkin J (1991) Microdialysis studies on 3,4-methylenedioxymethamphetamine-induced dopamine release: effect of dopamine uptake inhibitors. J Pharmacol Exp Ther 259:820–825

    Google Scholar 

  • Ng N-K, Lee H-S, Wong PT-H (1999) Regulation of striatal dopamine release through 5-HT1 and 5-HT2 receptors. J Neurosci Res 55:600–607

    Article  CAS  PubMed  Google Scholar 

  • Parrott AC (2002) Recreational ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity. Pharmacol Biochem Behav 71:837–844

    Article  CAS  PubMed  Google Scholar 

  • Pederson W, Skrondal A (1999) Ecstasy and new patterns of drug use: a normal population study. Addiction 94:1695–1706

    Article  CAS  PubMed  Google Scholar 

  • Piazza PV, Deminiere JM, Le Moal M, Simon H (1989) Factors that predict individual vulnerability to amphetamine self-administration. Science 245:1511

    CAS  PubMed  Google Scholar 

  • Pierre PJ, Vezina P (1997) Predisposition to self-administer amphetamine: the contribution of response to novelty and prior exposure to the drug. Psychopharmacology 129:277–284

    Article  CAS  PubMed  Google Scholar 

  • Pope HG, Ionescu-Pioggia M, Pope KW (2001) Drug use and life style among college undergraduates: a 30-year longitudinal study. Am J Psychiatry 158:1519–1521

    Article  PubMed  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  CAS  PubMed  Google Scholar 

  • Robinson TE, Becker JB (1986) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res 396:157–198

    CAS  PubMed  Google Scholar 

  • Rothman RB, Baumann MH, Dersch ChM, Romero DV, Rice KC, Carroll FI, Partilla JS (2001) Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 39:32–41

    CAS  PubMed  Google Scholar 

  • Rudnick G, Wall S (1992) The molecular mechanism of "ecstasy" [3,4-methylenedioxymethamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Proc Natl Acad Sci USA 89:1817–1821

    CAS  PubMed  Google Scholar 

  • Schenk S (2002) Sensitization as a process underlying the progression of drug use via "gateway" drugs. In: Kandel D (ed) Stages and pathways of drug involvement: examining the gateway hypothesis. Cambridge University Press, Cambridge, pp 318–336

    Google Scholar 

  • Schenk S, Partridge B (1997) Sensitization and tolerance in psychostimulant self-administration. Pharmacol Biochem Behav 57:543–550

    CAS  Google Scholar 

  • Schenk S, Partridge B (2000) Sensitization to cocaine's reinforcing effects produced by various cocaine pretreatment regimens in rats. Pharmacol Biochem Behav 66:765–770

    CAS  PubMed  Google Scholar 

  • Schenk S, Partridge B (2001) Influence of a conditioned light stimulus in cocaine self-administration. Psychopharmacology 154:390–396

    CAS  PubMed  Google Scholar 

  • Schenk S, Horger BA, Peltier R, Shelton K (1991) Supersensitivity to the reinforcing effects of cocaine following 6-hydroxydopamine lesions to the medial prefrontal cortex in rats. Brain Res 543:227–235

    CAS  PubMed  Google Scholar 

  • Schenk S, Valadez A, McNamara C, House D, Higley D, Bankson MT, Gibbs S, Horger BA (1993) Development and expression of sensitization to cocaine's reinforcing properties: role of NMDA receptors. Psychopharmacology 111:332–338

    CAS  PubMed  Google Scholar 

  • Schmidt CJ, Sullivan CK, Fadayel GN (1994) Blockade of striatal 5-HT2 receptors reduced the increase in extracellular concentrations of dopamine produced by the amphetamine analogue 3,4-methylenedioxymethamphetamine. J Neurochem 62:1382–1389

    CAS  PubMed  Google Scholar 

  • Schuster CR, Thompson T (1969) Self administration of and behavioral dependence on drugs. Annu Rev Pharmacol 9:483–502

    CAS  PubMed  Google Scholar 

  • Schuster P, Lieb R, Lamertz C, Wittchen HU (1998) Is the use of ecstasy and hallucinogens increasing? Results from a community study. Eur Addict Res 4:75–82

    CAS  PubMed  Google Scholar 

  • Siliquini R, Faggiano F, Geninatti S, Versino E, Mitola B, Ippolito R (2001) Patterns of drug use among young men in Piedmont (Italy). Drug Alcohol Depend 64:329–335

    Article  CAS  PubMed  Google Scholar 

  • Spanos LJ, Yamamoto BK (1989) Acute and subchronic effects of methylenedioxymethamphetamine [(±)MDMA] on locomotion and serotonin syndrome behavior in the rat. Pharmacol Biochem Behav 32:835–840

    Article  CAS  PubMed  Google Scholar 

  • Spruit IP (2001) Monitoring synthetic drug markets, trends, and public health. Subst Use Misuse 36:23–47

    Article  CAS  PubMed  Google Scholar 

  • Teter CJ, Guthrie SK (2001) A comprehensive review of MDMA and GHB: two common club drugs. Pharmacotherapy 21:1486–1513

    CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • Wise RA, Rompre P-P (1989) Brain dopamine and reward. Annu Rev Psychol 40:191–225

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Yan QS, Yan SE (2001) Activation of 5-HT(1B/1D) receptors in the mesolimbic dopamine system increases dopamine release from the nucleus accumbens: a microdialysis study. Eur J Pharmacol 418:55–64

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by research grants from Lottery Health, New Zealand, The Neurological Foundation of New Zealand and the University Research Fund, Victoria University of Wellington.

Author information

Authors and Affiliations

  1. School of Psychology, Victoria University of Wellington, PO Box 600, Wellington, New Zealand

    Susan Schenk, David Gittings, Malcolm Johnstone & Evangeline Daniela

Authors
  1. Susan Schenk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Gittings
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Malcolm Johnstone
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Evangeline Daniela
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susan Schenk.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schenk, S., Gittings, D., Johnstone, M. et al. Development, maintenance and temporal pattern of self-administration maintained by ecstasy (MDMA) in rats. Psychopharmacology 169, 21–27 (2003). https://doi.org/10.1007/s00213-003-1407-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-003-1407-0

Keywords

Search

Navigation