Skip to main content
SpringerLink
Log in

A role for the mesolimbic dopamine system in the psychostimulant actions of MDMA

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

Abstract

Methylenedioxymethamphetamine (MDMA) is a phenylethylamine with a chemical structure that resembles both the amphetamines and mescaline and has both stimulant and perception altering properties. The stimulant properties of MDMA were assessed in photocell cages designed to measure locomotor activity in rats. MDMA, over a range of doses (2.5–10.0 mg/kg, SC) produced locomotor hyperactivity which lasted up to 4 h. Further studies examined the role of the mesolimbic dopamine system in the hyperactivity induced by MDMA. 6-Hydroxydopamine lesions of the Nucleus accumbens attenuated the locomotor response produced by MDMA. The well characterized attenuation of the locomotor response produced by amphetamine was also demonstrated in the same rats. The present study demonstrates similarities in the stimulant properties of MDMA and amphetamine, and also suggests that as with amphetamine, the locomotor activation associated with MDMA may involve the presynaptic release of dopamine in the region of the Nucleus accumbens. However, MDMA may have a more unusual pharmacological profile because of its longer duration of action, neurotoxic potential, and differences in the qualitative aspects of its psychoactive effects.

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

Similar content being viewed by others

References

  • Barnes D (1988) New data intensify the agony over Ecstasy. Science 239:864–866

    Google Scholar 

  • Battaglia G, Yeh SY, O'Hearn E, Molliver ME, Kuhar MJ, De Souza EB (1987) 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. J Pharmacol Exp Ther 242:911–916

    Google Scholar 

  • Battaglia G, Brooks B, Kulsakdinum C, De Souza EB (1988) Pharmacologic profile of MDMA (3,4-methylenedioxymethamphetamine) at various brain recognition sites. Eur J Pharmacol 149:159–163

    Google Scholar 

  • Beardsley P, Balster R, Harris L (1986) Self-administration of methylenedioxymethamphetamine (MDMA) by Rhesus monkeys. Drug Alcohol Depend 18:149–157

    Google Scholar 

  • Beck J, Morgan P (1986) Designer drug confusion: a focus on MDMA. J Drug Educ 16:287–302

    Google Scholar 

  • Bloom FE, Algeri S, Gropetti A, Revuelta A, Costa E (1969) Lesions of central norepinephrine terminals with 6-OH-dopamine: biochemistry and fine structure. Science 166:1284–1286

    Google Scholar 

  • Braun U, Shulgin A, Braun G (1980) Centrally active N-substituted analogs of 3,4-methylenedioxyphenylisopropylamine (3,4-methylenedioxyamphetamine). J Pharm Sci 69:192–195

    Google Scholar 

  • Callahan PM, Appel JB (1987) Differences in the stimulus properties of MDA and MDMA in animals trained to discriminate hallucinogens from saline. Soc Neurosci Abstr 13:1720

    Google Scholar 

  • Clarke PBS, Jakubovic A, Fibiger HC (1988) Anatomical analysis of the involvement of mesolimbocortical dopamine in the locomotor stimulant actions ofd-amphetamine and apomorphine. Psychopharmacology 96:511–520

    Google Scholar 

  • Commins DL, Vosmer G, Virus RM, Woolverton WL, Schuster CR, Seiden LS (1987) Biochemical and histological evidence that methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain. J Pharmacol Exp Ther 241:338–345

    Google Scholar 

  • Creese I, Iversen SD (1975) The pharmacological and anatomical substrates of the amphetamine response in the rat. Brain Res 83:419–436

    Google Scholar 

  • Dowling GP, McDonough ET, Bost RO (1987) “Eve” and “Ecstasu” A report of five deaths associated with the use of MDEA and MDMA. JAMA 257:11615–1617

    Google Scholar 

  • Felice L, Felice J, Kissinger P (1978) Determination of catecholamines in rat brain parts by reverse-phase ion-pair liquid chromatography. J Neuorchem 31:1461–1465

    Google Scholar 

  • File SJ (1981) Pharmacological manipulations of responses to novelty and their habituation. In: Cooper SJ (ed) Theory in psychopharmacology, vol 1. Academic Press, London, pp 197–232

    Google Scholar 

  • Fishman RHB, Feigenbaum JJ, Yanai J, Klawans HL (1983) The relative importance of dopamine and norepinephrine in mediating locomotor activity. Prog Neurobiol 20:55–88

    Google Scholar 

  • Geyer MA, Puerto A, Menkes DB, Segal DS, Mandell AJ (1976) Behavioral studies following lesions of the mesolimbic and mesostriatal serotonergic pathways. Brain Res 106:257–270

    Google Scholar 

  • Geyer MA, Masten VL, Segal DS (1986) Behavioral effects of xylamine-induced depletions of brain norepinephrine: interaction with amphetamine. Behav Brain Res 21:55–64

    Google Scholar 

  • Glennon RA, Yousif M, Patrick G (1988) Stimulus properties of I-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) analogs. Pharmacol Biochem Behav 29:443–449

    Google Scholar 

  • Gold LH, Koob GF (1988) Methysergide potentiates the hyperactivity produced by MDMA in rats. Pharmacol Biochem Behav 29:645–648

    Google Scholar 

  • Gold LH, Koob GF, Geyer MA (1988) Stimulant and hallucinogenic behavioral profiles of 3,4-methylenedioxymethamphetamine (MDMA) and N-ethyl-3,4-methylenedioxyamphetamine (MDE) in rats. J Pharmacol Exp Ther 247:547–555

    Google Scholar 

  • Grinspoon L, Bakalar J (1986) Can drugs be used to enhance the psychotherapeutic process? Am J Psychother XL:393–404

    Google Scholar 

  • Herve D, Studler JM, Blanc G, Glowinski J, Tassin JP (1986) Partial protection by desmethylimipramine of the mesocortical dopamine neruones from the neurotoxic effect of 6-hydroxydopamine injected in ventral mesencephalic tegmentum. The role of noradrenergic innervation. Brain Res 383:47–53

    Google Scholar 

  • Hollister AG, Breese C, Moreton Kuhn C, Cooper B, Schanberg S (1976) An inhibitory role for brain serotonin-containing systems in the locomotor effects ofd-amphetamine. J Pharmacol Exp Ther 198:12–22

    Google Scholar 

  • Hubner CB, Bird M, Rassnick S, Kornetsky C (1988) The threshold lowering effects of MDMA (ecstasy) on brain-stimulation reward. Psychopharmacology 95:49–51

    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

    Google Scholar 

  • Joyce EM, Koob GF (1981) Amphetamine-, scopolamine-, and caffeine-induced locomotor activity following 6-hydroxydopamine lesions of the mesolimbic dopamine system. Psychopharmacology 73:311–313

    Google Scholar 

  • Kelly PH, Iversen SD (1976) Selective 6OHDA-induced destruction of mesolimbic dopamine neurons: abolition of psychostimulant-induced locomotor activity in rats. Eur J Pharmacol 40:45–56

    Google Scholar 

  • Kelly PH, Seviour P, Iversen SD (1975) Amphetamine and apomorphine response in the rat following 6-OHDA lesions of the Nucleus accumbens septi and corpus striatum. Brain Res 94:507–522

    Google Scholar 

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

    Google Scholar 

  • Li A, Marek G, Vosmer G, Seiden L (1986) MDMA-induced serotonin depletion potentiates the psychomotor stimulant effects of MDMA on rats performing on the differential-reinforcement of-low-rate (DRL) schedule. Soc Neurosci Abstr 12:609

    Google Scholar 

  • Mokler DJ, Robinson SE, Rosecrans JA (1987) (±)3,4-Methylenedioxymethamphetamine (MDMA) produces long-term reductions in brain 5-hydroxytryptamine in rats. Eur J Pharmacol 138:265–268

    Google Scholar 

  • Nichols DE, Lloyd DH, Hoffman AJ, Nichols MB, Yim GKW (1982) Effects of certain hallucinogenic amphetamine analogues on the release of [3H] serotonin from rat brain synaptosomes. J Med Chem 25:530–535

    Google Scholar 

  • Nichols DE, Hoffman AJ, Oberlender RA, Jacob P, Shulgin AT (1986) Derivatives of 1-(1,3-benzodioxol-5-yl)-2-butanamine: representatives of a novel therapeutic class. J Med Chem 29:2009–2015

    Google Scholar 

  • Oberlender R, Nichols DE (1988) Drug discrimination studies with MDMA and amphetamine. Psychopharmacology 95:71–76

    Google Scholar 

  • Onn S-P, Berger T, Stricker EM, Zigmond MJ (1986) Effects of intraventricular 6-hydroxydopamine on the dopaminergic innervation of striatum: histochemical and neurochemical analysis. Brain Res 376:8–19

    Google Scholar 

  • Peroutka S (1987) Incidence of recreational use of 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) on an undergraduate campus. New Engl J Med 317:1542–1543

    Google Scholar 

  • Peroutka SJ, Newman H, Harris H (1988) Subjective effects of 3,4-methylenedioxymethamphetamine in recreational users. Neuropsychopharmacology 1:273–277

    Google Scholar 

  • Pettit HO, Ettenberg A, Bloom FE, Koob GF (1984) Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats. Psychopharmacology 84:167–173

    Google Scholar 

  • Roberts DC, Koob GF, Klonoff P, Fibiger HC (1980) Extinction and recovery of cocaine self-administration following 6-hydroxydopamine lesions of the Nucleus accumbens. Pharmacol Biochem Behav 12:781–787

    Google Scholar 

  • Roberts DCS, Zis AP, Fibiger HC (1975) Ascending catecholamine pathways and amphetamine-induced locomotor activity: importance of dopamine and apparent non-involvement of norepinephrine. Brain Res 93:441–454

    Google Scholar 

  • Sachs C, Jonsson G (1975) Mechanisms of action of 6-hydroxydopamine. Biochem Pharmacol 24:1–8

    Google Scholar 

  • Schechter M (1986) Discriminative profile of MDMA. Pharmacol Biochem Behav 24:1533–1537

    Google Scholar 

  • Schmidt C (1987a) Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. J Pharmacol Exp Ther 240:1–7

    Google Scholar 

  • Schmidt C (1987b) Acute administration of methylenedioxymethamphetamine: comparison with the neurochemical effects of its N-desmethyl and N-ethyl analogs. Eur J Pharmacol 136:81–88

    Google Scholar 

  • Schmidt CJ, Wu L, Lovenberg W (1986) Methylenedioxymethamphetamine: a potentially neurotoxic amphetamine analogue. Eur J Pharmacol 124:175–178

    Google Scholar 

  • Schmidt CJ, Levin JA, Lovenberg W (1987) In vitro and in vivo neurochemical effects of MDMA on striatal monoaminergic systems in rat brain. Biochem Pharmacol 36:747–755

    Google Scholar 

  • Shulgin AT, Nichols DE (1978) Characterization of three new psychotomimetics. In: Stillman RC, Willette RE (eds) The pharmacology of hallucinogens. Pergamon Press, New York, pp 74–83

    Google Scholar 

  • Steele TD, Nichols DE, Yim GK (1987) Stereochemical effects of 3,4-methylenedioxymethamphetamine (MDMA) and related amphetamine derivatives on inhibition of uptake of [3H]monoamines into synaptosomes from different regions of rat brain. Biochem Pharmacol 36:2297–2303

    Google Scholar 

  • Stone D, Stahl D, Hanson G, Gibb J (1986) The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain. Eur J Pharmacol 128:41–48

    Google Scholar 

  • Stone DM, Johnson M, Hanson GR, Gibb JW (1988) Role of endogenous dopamine in the central serotonergic deficits induced by 3,4-methylenedioxymethamphetamine J Pharmacol Exp Ther 247:79–87

    Google Scholar 

  • Swanson LW, Hartman BK (1975) The central adrenergic system. An immunofluorescence study of the location of cell bodies and their efferent connections in the rat utilizing dopamine-β-hydroxylase as a marker. J Comp Neurol 163:467–506

    Google Scholar 

  • Swerdlow NR, Vaccarino FJ, Amalric M, Koob GF (1986) The neural substrates for the motor-activating properties of psychostimulants: a review of recent findings. Pharmacol Biochem Behav 25:233–248

    Google Scholar 

  • Tassin JP, Simon H, Herve D, Blanc G, Le Moal M, Glowinski J, Bockaert J (1982) Non-dopaminergic fibres may regulate dopamine-sensitive adenylate cyclase in the prefrontal cortex and Nucleus accumbens. Nature 295:696–698

    Google Scholar 

  • Thornbrug JE, Moore KE (1973) The relative importance of dopaminergic and noradrenergic neuronal systems for the stimulation of locomotor activity induced by amphetamine and other drugs. Neuropharmacology 12:853–866

    Google Scholar 

  • Vaccarino FJ, Amalric M, Swerdlow NR, Koob GF (1986) Blockade of amphetamine but not opiate induced locomotion following antagonism of dopamine function in the rat. Pharmacol Biochem Behav 24:61–65

    Google Scholar 

  • Versteeg DHG, Van der Gugten J, De Jong WS, Palkovits M (1976) Regional concentrations of noradrenaline and dopamine in rat brain. Brain Res 113:563–574

    Google Scholar 

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

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Basic and Clinical Research, Research Institute of Scripps Clinic, 10666 North Torrey Pines Road, 92037, La Jolla, CA, USA

    Lisa H. Gold, Carol B. Hubner & George F. Koob

Authors
  1. Lisa H. Gold
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carol B. Hubner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. George F. Koob
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This is publication number5455BCR from the Research Institute of Scripps Clinic

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gold, L.H., Hubner, C.B. & Koob, G.F. A role for the mesolimbic dopamine system in the psychostimulant actions of MDMA. Psychopharmacology 99, 40–47 (1989). https://doi.org/10.1007/BF00634450

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00634450

Key words

Search

Navigation