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.
Similar content being viewed by others
References
Barnes D (1988) New data intensify the agony over Ecstasy. Science 239:864–866
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
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
Beardsley P, Balster R, Harris L (1986) Self-administration of methylenedioxymethamphetamine (MDMA) by Rhesus monkeys. Drug Alcohol Depend 18:149–157
Beck J, Morgan P (1986) Designer drug confusion: a focus on MDMA. J Drug Educ 16:287–302
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
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
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
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
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
Creese I, Iversen SD (1975) The pharmacological and anatomical substrates of the amphetamine response in the rat. Brain Res 83:419–436
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
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
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
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
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
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
Glennon RA, Yousif M, Patrick G (1988) Stimulus properties of I-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) analogs. Pharmacol Biochem Behav 29:443–449
Gold LH, Koob GF (1988) Methysergide potentiates the hyperactivity produced by MDMA in rats. Pharmacol Biochem Behav 29:645–648
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
Grinspoon L, Bakalar J (1986) Can drugs be used to enhance the psychotherapeutic process? Am J Psychother XL:393–404
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
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
Hubner CB, Bird M, Rassnick S, Kornetsky C (1988) The threshold lowering effects of MDMA (ecstasy) on brain-stimulation reward. Psychopharmacology 95:49–51
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
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
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
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
Lamb R, Griffiths R (1987) Self-injection ofd-1-3,4-methylenedioxymethamphetamine (MDMA) in the baboon. Psychopharmacology 91:268–272
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
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
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
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
Oberlender R, Nichols DE (1988) Drug discrimination studies with MDMA and amphetamine. Psychopharmacology 95:71–76
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
Peroutka S (1987) Incidence of recreational use of 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) on an undergraduate campus. New Engl J Med 317:1542–1543
Peroutka SJ, Newman H, Harris H (1988) Subjective effects of 3,4-methylenedioxymethamphetamine in recreational users. Neuropsychopharmacology 1:273–277
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
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
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
Sachs C, Jonsson G (1975) Mechanisms of action of 6-hydroxydopamine. Biochem Pharmacol 24:1–8
Schechter M (1986) Discriminative profile of MDMA. Pharmacol Biochem Behav 24:1533–1537
Schmidt C (1987a) Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. J Pharmacol Exp Ther 240:1–7
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
Schmidt CJ, Wu L, Lovenberg W (1986) Methylenedioxymethamphetamine: a potentially neurotoxic amphetamine analogue. Eur J Pharmacol 124:175–178
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
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
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
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
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
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
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
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
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
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
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
Yamamoto JK, Spanos LJ (1988) The acute effects of methylenedioxymethamphetamine on dopamine release in the awake-behaving rat. Eur J Pharmacol 148:195–203
Author information
Authors and Affiliations
Additional information
This is publication number5455BCR from the Research Institute of Scripps Clinic
Rights 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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00634450