Journal Mobile Options
Table of Contents
Vol. 31, No. 1-2, 2009
Issue release date: April 2009
Dev Neurosci 2009;31:107–120

(+/–)3,4-Methylenedioxymethamphetamine (MDMA) Dose-Dependently Impairs Spatial Learning in the Morris Water Maze after Exposure of Rats to Different Five-Day Intervals from Birth to Postnatal Day Twenty

Vorhees C.V. · Schaefer T.L. · Skelton M.R. · Grace C.E. · Herring N.R. · Williams M.T.
Division of Neurology, Department of Pediatrics and Cincinnati Children’s Research Foundation, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


During postnatal days (PD) 11–20, (+/–)3,4-methylenedioxymethamphetamine (MDMA) treatment impairs egocentric and allocentric learning, and reduces spontaneous locomotor activity; however, it does not have these effects during PD 1–10. How the learning impairments relate to the stress hyporesponsive period (SHRP) is unknown. To test this association, the preweaning period was subdivided into 5-day periods from PD 1–20. Separate pups within each litter were injected subcutaneously with 0, 10, 15, 20, or 25 mg/kg MDMA ×4/day on PD 1–5, 6–10, 11–15, or 16–20, and tested as adults. The 3 highest MDMA dose groups showed reduced locomotor activity during the first 10 min (of 60 min), especially in the PD 1–5 and 6–10 dosing regimens. MDMA groups in all dosing regimens showed impaired allocentric learning in the Morris water maze (on acquisition and reversal, all MDMA groups were affected; on the small platform phase, the 2 high-dose groups were affected). No effects of MDMA were found on anxiety (elevated zero maze), novel object recognition, or egocentric learning (although a nonsignificant trend was observed). The Morris maze results did not support the idea that the SHRP is critical to the effects of MDMA on allocentric learning. However, since no effects on egocentric learning were found, but were apparent after PD 11–20 treatment, the results show that these 2 forms of learning have different exposure-duration sensitivities.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Akaike M, Kato N, Ohno H, Kobayashi T (1991): Hyperactivity and spatial maze learning impairment of adult rats with temporary neonatal hypothyroidism. Neurotoxicol Teratol 13:317–322.
  2. Bayer SA, Altman J, Russo RJ, Zhang X (1993): Timetables of neurogenesis in the human brain based on experimentally determined patterns in the rat. Neurotoxicology 14:83–144.
  3. Broening HW, Bacon L, Slikker W Jr (1994): Age modulates the long-term but not the acute effects of the serotonergic neurotoxicant 3,4-methenedioxymethamphetamine. J Pharmacol Exp Ther 271:285–293.
  4. Broening HW, Bowyer JF, Slikker W Jr (1995): Age dependent sensitivity of rats to the long-term effects of the serotonin neurotoxicant (+/–)-3,4-methylenedioxymethamphetamine (MDMA) correlates with the magnitude of the MDMA-induced thermal response. J Pharmacol Exp Ther 275:325–333.
  5. Broening HW, Morford LL, Inman-Wood SL, Fukumura M, Vorhees CV (2001): 3,4-methylenedioxymethamphetamine (ecstasy) induced learning and memory impairments depend on the age of exposure during early development. J Neurosci 21:3228–3235.
  6. Clancy B, Finlay BL, Darlington RB, Anand KJ (2007a): Extrapolating brain development from experimental species to humans. Neurotoxicology 28:931–937.
  7. Clancy B, Kersh B, Hyde J, Darlington RB, Anand KJ, Finlay BL (2007b): Web-based method for translating neurodevelopment from laboratory species to humans. Neuroinformatics 5:79–94.
  8. Clark RE, Zola SM, Squire LR (2000): Impaired recognition memory in rats after damage to the hippocampus. J Neurosci 20:8853–8860.
  9. Cohen MA, Skelton MR, Schaefer TL, Gudelsky GA, Vorhees CV, Williams MT (2005) Learning and memory after neonatal exposure to 3,4-methylenedioxymethamphetamine (ecstasy) in rats: interaction with exposure in adulthood. Synapse 57:148–159.
  10. Crawford CA, Williams MT, Kohutek JL, Choi FY, Yoshida ST, McDougall SA, Vorhees CV (2006): Neonatal 3,4-methylenedioxymethamphetamine (MDMA) exposure alters neuronal protein kinase A activity, seroto- nin and dopamine content, and [35S]GTP- gammaS binding in adult rats. Brain Res 1077:178–186.
  11. De La Torre R, Farre M (2003): Neurotoxicity of MDMA (ecstasy): the limitations of scaling from animals to humans. Trends Pharmacol Sci 2004;25:505–508.
  12. Green AR, Mechan AO, Elliott JM, O’Shea E, Colado MI (2003): The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’). Pharmacol Rev 55:463–508.
  13. Herlenius E, Lagercrantz H (2004): Development of neurotransmitter systems during critical periods. Exp Neurol 190:S8–S21.
  14. Ho E, Karimi-Tabesh L, Koren G (2001): Characteristics of pregnant women who use ecstasy (3,4-methylenedoxymethamphetamine). Neurotoxicol Teratol 23:561–567.
  15. Irvine RJ, Keane M, Felgate P, McCann UD, Callaghan PD, White JM (2006): Plasma drug concentrations and physiological measures in ‘dance party’ participants. Neuropsychopharmacology 31:424–430.
  16. Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE (2007): Monitoring the Future: national survey results on drug use, 1975–2006. Vol. II: college students and adults ages 19–45. Bethesda, National Institute on Drug Abuse – US Department of Health and Human Services.
  17. Kelly PAT, Ritchie IM, Quate L, McBean DE, Olverman HJ, Aase JM (2002): Functional consequences of perinatal exposure to 3,4-methylenedioxymethamphetamine in rat brain. Br J Pharmacol 137:963–970.
  18. Koprich JB, Chen E-Y, Kanaan NM, Campbell NG, Kordower JH, Lipton JW (2003): Prenatal 3,4-methylenedioxymethamphetamine (ecstasy) alters exploratory behavior, reduces monoamine metabolism, and increases forebrain tyrosine hydroxylase fiber density of juvenile rats. Neurotoxicol Teratol 25:509–517.
  19. Liu H, Kaur J, Dashtipour K, Kinyamu R, Ribak CE, Friedman LK (2003): Suppression of hippocampal neurogenesis is associated with developmental stage, number of perinatal seizure episodes, and glucocorticosteroid level. Exp Neurol 184:196–213.
  20. McElhatton PR, Bateman DN, Evans C, Pughe KR, Thomas SH (1999): Congenital anomalies after prenatal ecstasy exposure. Lancet 354:1441–1442.
  21. Meaney MJ, Aitken DH, van Berkel C, Bhatnager S, Sapolsky RM (1988): Effect of neonatal handling on age-related impairments associated with the hippocampus. Science 239:766–768.
  22. Meyer JS, Ali SF (2002): Serotonergic neurotoxicity of MDMA (ecstasy) in the developing rat brain. Ann NY Acad Sci 965:373–380.
  23. Meyer JS, Grande M, Johnson K, Ali SF (2004): Neurotoxic effects of MDMA (‘ecstasy’) administration on neonatal rats. Int J Dev Neurosci 22:261–271.
  24. Parrott AC (2005): Chronic tolerance to recreational MDMA (3,4-methylenedioxymethamphetamine) or ecstasy. J Psychopharmacol 19:71–83.
  25. Rice D, Barone S Jr (2000): Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 108:511–533.
  26. Sapolsky RM (1996): Stress, glucocorticoids, and damage to the nervous system: the current state of confusion. Stress 1:1–19.
  27. Sapolsky RM, Meaney MJ (1986): Maturation of the adrenocortical stress response: neuroendocrine control mechanisms and the stress hyporesponsive period. Brain Res Rev 11:65–76.
  28. Schaefer TL, Ehrman LA, Gudelsky GA, Vorhees CV, Williams MT (2006a): Comparison of monoamine and corticosterone levels 24 h following (+)methamphetamine, (+/–)3,4-methylenedioxymethamphetamine, cocaine, (+)fenfluramine or (+/–)methylphenidate administration in the neonatal rat. J Neurochem 98:1369–1378.
  29. Schaefer TL, Herring NR, Grace CE, Skelton MR, Johnson HL, Vorhees CV, Williams MT (2006b): A comparison of preweaning 5-methoxy-diisopropyltryptamine and (±)3,4-methylenedioxymethamphetamine administration on postweaning anxiety, learning and locomotor activity in rats. Abstr Soc Neurosci, Atlanta, October 2006.
  30. Schaefer TL, Skelton MR, Herring NR, Gudelsky GA, Vorhees CV, Williams MT (2008): Short- and long-term effects of (+)-methamphetamine and (+/–)-3,4-methylenedioxymethamphetamine on monoamine and corticosterone levels in the neonatal rat following multiple days of treatment. J Neurochem 104:1674–1685.
  31. Shepherd JK, Grewal SS, Fletcher A, Bill DJ, Dourish CT (1994): Behavioural and pharmacological characterization of the elevated ‘zero-maze’ as an animal model of anxiety. Psychopharmacology 116:56–64.
  32. Skelton MR, Williams MT, Vorhees CV (2006): Treatment with MDMA from P11–20 disrupts spatial learning and path integration learning in adolescent rats but only spatial learning in older rats. Psychopharmacology (Berlin) 189:307–318.
  33. Skelton MR, Williams MT, Vorhees CV (2008): Developmental effects of 3,4-methylenedioxymethamphetamine: a review. Behav Pharmacol 19:91–111.
  34. St. Omer VE, Ali SF, Holson RR, Scalzo FM, Slikker W Jr. (1991): Behavioral and neurochemical effects of prenatal methylenedioxymethamphetamine (MDMA) exposure in rats. Neurotoxicol Teratol 13:13–20.
  35. Vazquez DM (1998): Stress and the developing limbic-hypothalamic-pituitary-adrenal axis. Psychoneuroendocrinology 23:663–700.
  36. Vorhees CV (1987): Maze learning in rats: a comparison of performance in two water mazes in progeny prenatally exposed to different doses of phenytoin. Neurotoxicol Teratol 9:235–241.
  37. Vorhees CV, Reed TM, Skelton MR, Williams MT (2004): Exposure to 3,4-methylenedioxymethamphetamine (MDMA) on postnatal days 11–20 induces reference but not working memory deficits in the Morris water maze in rats: implications of prior learning. Int J Dev Neurosci 22:247–259.
  38. Vorhees CV, Schaefer TL, Williams MT (2007): Developmental effects of +/–3,4-methylenedioxymethamphetamine on spatial versus path integration learning: effects of dose distribution. Synapse 61:488–499.
  39. Vorhees CV, Williams MT (2006): Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protocols 1:848–858.
  40. West JR, Pierce DR (1987): Perinatal alcohol exposure and neuronal damage; in West JR (ed): Alcohol and Brain Development. New York, Oxford University Press, pp 120–157.
  41. Williams MT, Brown CA, Skelton MR, Vinks AA, Vorhees CV (2004): Absorption and clearance of ±3,4-methylenedioxymethamphetamine from the plasma of neonatal rats. Neurotoxicol Teratol 26:849–856.
  42. Williams MT, Moran MS, Vorhees CV (2003a): Refining the critical period for methamphetamine-induced spatial deficits in the Morris water maze. Psychopharmacology 168:329–338.
  43. Williams MT, Morford LL, Wood SL, Rock SL, McCrea AE, Fukumura M, Wallace TL, Broening HW, Moran MS, Vorhees CV (2003b): Developmental 3,4-methylenedioxymethamphetamine (MDMA) impairs sequential and spatial but not cued learning independent of growth, litter effects, or injection stress. Brain Res 968:89–101.
  44. Williams MT, Schaefer TL, Furay AR, Ehrman LA, Vorhees CV (2006): Ontogeny of the adrenal response to (+)-methamphetamine in neonatal rats: the effect of prior drug exposure. Stress 9:153–163.
  45. Winslow JT, Insel TR (1990): Serotonergic modulation of rat pup ultrasonic vocal development: studies with 3,4-methylendioxymethamphetamine. J Pharmacol Exp Ther 254:212–220.
  46. Won L, Bubula N, Heller A (2002): Fetal ex- posure to (±)-methylenedoxymethamphetamine in utero enhances the development and metabolism of serotonergic neurons in three-dimensional reaggregate tissue culture. Dev Brain Res 137:67–73.

Pay-per-View Options
Direct payment This item at the regular price: USD 9.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 8.00