Abstract
The effect of the psychomotor stimulant, 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”), upon integrated cerebral function was measured in rats using the quantitative [14C]deoxyglucose autoradiographic technique. Animals were injected with MDMA (20 mg/kg sc) twice daily for 4 days. Fourteen days after the final administration, [3H]-paroxetine binding to 5HT uptake sites was reduced by 89% in membranes prepared from tissue samples of frontal cortex. In the same rats [3H]-paroxetine binding autoradiography revealed heterogeneity in the regional distribution of 5-HT uptake site depletion within neocortex (0–92%) and hippocampus (30–95%). Despite these profound reductions in 5-HT uptake sites no significant alterations were found in glucose utilisation in any area of neocortex examined. However, significant increases in glucose use were found in subregions of the hippocampus, most notably within the pyramidal cell layer of CA2 and CA3 (25–35%). This study provides direct evidence that the loss of 5-HT innervation caused by exposure to MDMA results in lasting functional changes in hippocampus.
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Battaglia G, Yeh SY, O'Hearn E, Molliver ME, Kuhar MJ, DeSouza 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, Sharkey J, Kuhar MJ, DeSouza EB (1988a) Neuroanatomical specificity of MDA and MDMA-induced degeneration of serotonin neurones in rat brain. Soc Neurosci Abstr 14:222.5
Battaglia G, Yeh SY, DeSouza EB (1988b) MDMA-induced neurotoxicity: parameters of degeneration and recovery of brain serotonin systems. Pharmacol Biochem Behav 29:269–274
Chalmers DT, McCulloch J (1989) Excitatory amino acid receptor sites and glucose use after acute orbital enucleation J Cereb Blood Flow Metab 9[Suppl. 1]:s299
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
Cudennec A, Duverger D, Nishikawa T, McRae-Degueurce A, MacKenzie ET, Scatton B (1988a) Influence of ascending serotonergic pathways on glucose use in the conscious rat brain. II. Effects of electrolytic or neurotoxic lesions of the dorsal and/or median raphe nucleus. Brain Res 444:214–226
Cudennec A, Duverger D, Serrano A, Scatton B, MacKenzie ET (1988b) Influence of ascending serotonergic pathways on glucose use in the conscious rat brain. II. Effects of electrical stimulation of the rostral raphe nuclei. Brain Res 444:227–246
De Souza EB, Kuyatt BL (1987) Autoradiographic localization of 3H-paroxetine labeled serotonin uptake sites in rat brain. Synapse 1:488–496
Dowling J (1986) The psychological and physiological effects of MDMA on normal volunteers. J Psychoactive Drugs 18:335–340
Gibb JW, Stone DM, Stahl DC, Hanson GR (1987) The effect of amphetamine-like designer drugs on monoaminergic systems in rat brain. Natl Inst Drug Abuse Res Monogr Ser 76:316–321
Glennon RA, Young R (1984) MDA: an agent that produces stimulus effects similar to those of 3,4-DMA, LSD and cocaine. Eur J Pharmacol 99:249–250
Grinspoon L, Bakalar JB (1986) Can drugs be used to enhance the psychotherapeutic process? Am J Psychother 40:393–404
Habert E, Graham D, Tahraoui L, Claustre Y, Langer SZ (1985) Characterization of [3H]paroxetine binding to rat cortical membranes. Eur J Pharmacol 118:107–114
Kosofsky BE, Molliver ME (1987) The serotonergic innervation of cerebral cortex: different classes of axon terminals arise from dorsal and median raphe nuclei. Synapse 1:153–168
London ED, Wilkerson G, Ori C, Kimes AS (1990) Central action of psychomotor stimulants on glucose utilisation in extrapyramidal motor areas of the rat brain. Brain Res 512:155–158
Meltzer H (1989) Serotonergic dysfunction in depression. Br J Psychiatry Suppl Dec [8]:25–31
Molliver ME (1987) Serotonergic neuronal systems: what their anatomical organization tells us about function. J Clin Psychopharmacol 7:3s-23s
Munson P, Rodbard D (1980) LIGAND: a versatile computerised approach for the characterisation of ligand binding systems. Anal Biochem 107:220–239
O'Hearn E, Battaglia G, DeSouza EB, Kuhar MJ, Molliver ME (1988) Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity. J Neurosci 8:2788–2803
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press, New York
Peroutka SJ (1987) Incidence of recreational use of 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) on an undergraduate campus. N Engl J Med 317:1542–1543
Ricaurte GA, Forno LS, Wilson MA, De Lanney LE, Irwin I, Molliver ME, Langston JW (1988) (±)3,4-methylenedioxymethamphetamine selectively damages central serotonergic neurons in non-human primates. JAMA 260:51–55
Schmidt CJ, Taylor, VL (1988) Direct central effects of acute methylenedioxymethamphetamine on serotonergic neurons. Eur J Pharmacol 156:121–131
Shulgin AT (1986) The background and chemistry of MDMA. J Psychoactive Drugs 18:291–300
Siegel RK (1986) MDMA. Nonmedical use and intoxication. J Psychoactive Drugs 18:349–354
Slikker W, Holson RR, Ali SF, Kolta MG, Paule MG, Scallet AC, McMillan DE, Bailey JR, Hong JS, Scalzo FM (1989) Behavioral and neurochemical effects of orally administered MDMA in the rodent and non-human primate. Neurotoxicology 10:529–542
Sokoloff L (1977) Relationship between physiological function and energy metabolism in the central nervous system. J Neurochem 29:13–26
Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M (1977) The [14C]-deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28:897–916
Stone DM, Stahl DC, Hanson GR, Gibb JW (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
Treiser SL, Cascio GS, O'Donohue TL, Thoa NB, Jacobowitz DM, Keller KJ (1981) Lithium increases serotonin release and decreases serotonin receptors in hippocampus. Science 213:1529–1531
Welner SA, De Montigny C, Desroches J, Desjardins P, SuranyiCadotte BE (1989) Autoradiographic quantification of serotonin 1A receptors in rat brain following antidepressant drug treatment. Synapse 4:347–352
Wilkerson G, London ED (1989) Effects of methylenedioxymethamphetamine on local cerebral glucose utilization in the rat. Neuropharmacology 28:1129–1138
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Sharkey, J., McBean, D.E. & Kelly, P.A.T. Alterations in hippocampal function following repeated exposure to the amphetamine derivative methylenedioxymethamphetamine (“Ecstasy”). Psychopharmacology 105, 113–118 (1991). https://doi.org/10.1007/BF02316872
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DOI: https://doi.org/10.1007/BF02316872