Recreational drug use among pregnant women is a source of concern due to potential harmful effects of drug exposure on prenatal and infant development. The simultaneous abuse of ecstasy [3,4-methylenedioxymethamphetamine (MDMA)] and alcohol is prevalent among young adults, including young expectant mothers. Here, we used a rat model to study the potential risks associated with exposure to alcohol and MDMA during pregnancy. Pregnant rats received alcohol, MDMA, or both alcohol and MDMA by gavage at E13 through E15 twice daily. Female offspring treated prenatally with the combination of alcohol and MDMA, but not those exposed to either drug separately, showed at 3 months of age decreased exploratory activity and impaired working memory function. Prenatal treatment with the combination of alcohol and MDMA decreased proliferation of neuronal precursors in the adult dentate gyrus of the hippocampus, as measured by 5-bromo-2-deoxyuridine labelling, and adult neurogenesis, assessed by quantifying doublecortin expression. These results provide the first evidence that the simultaneous abuse of alcohol and ecstasy during pregnancy, even for short periods of time, may cause significant abnormalities in neurocognitive development.

1.
Bedi G, Van Dam NT, Redman J: Ecstasy (MDMA) and high prevalence psychiatric symptomatology: somatic anxiety symptoms are associated with polydrug, not ecstasy, use. J Psychopharmacol 2010;24:233-240.
2.
Singer LT, Moore DG, Fulton S, Goodwin J, Turner JJ, Min MO, Parrott AC: Neurobehavioral outcomes of infants exposed to MDMA (ecstasy) and other recreational drugs during pregnancy. Neurotoxicol Teratol 2012;34:303-310.
3.
Ho E, Karimi-Tabesh L, Koren G: Characteristics of pregnant women who use ecstasy (3, 4-methylenedioxymethamphetamine). Neurotoxicol Teratol 2001;23:561-567.
4.
Mohamed WM, Ben HS, Cassel JC, de Vasconcelos AP, Jones BC: MDMA: interactions with other psychoactive drugs. Pharmacol Biochem Behav 2011;99:759-774.
5.
Hernandez-Rabaza V, Navarro-Mora G, Velazquez-Sanchez C, Ferragud A, Marin MP, Garcia-Verdugo JM, Renau-Piqueras J, Canales JJ: Neurotoxicity and persistent cognitive deficits induced by combined MDMA and alcohol exposure in adolescent rats. Addict Biol 2010;15:413-423.
6.
Campbell NG, Koprich JB, Kanaan NM, Lipton JW: MDMA administration to pregnant Sprague-Dawley rats results in its passage to the fetal compartment. Neurotoxicol Teratol 2006;28:459-465.
7.
Galineau L, Belzung C, Kodas E, Bodard S, Guilloteau D, Chalon S: Prenatal 3,4-methylenedioxymethamphetamine (ecstasy) exposure induces long-term alterations in the dopaminergic and serotonergic functions in the rat. Brain Res Dev Brain Res 2005;154:165-176.
8.
Koprich JB, Chen EY, Kanaan NM, Campbell NG, Kordower JH, Lipton JW: Prenatal 3,4-methylenedioxymethamphetamine (ecstasy) alters exploratory behavior, reduces monoamine metabolism, and increases forebrain tyrosine hydroxylase fiber density of juvenile rats. Neurotoxicol Teratol 2003;25:509-517.
9.
Thompson VB, Koprich JB, Chen EY, Kordower JH, Terpstra BT, Lipton JW: Prenatal exposure to MDMA alters noradrenergic neurodevelopment in the rat. Neurotoxicol Teratol 2012;34:206-213.
10.
Heuland E, Germaux MA, Galineau L, Chalon S, Belzung C: Prenatal MDMA exposure delays postnatal development in the rat: a preliminary study. Neurotoxicol Teratol 2010;32:425-431.
11.
Skelton MR, Williams MT, Vorhees CV: Developmental effects of 3,4-methylenedioxymethamphetamine: a review. Behav Pharmacol 2008;19:91-111.
12.
Goodlett CR, Horn KH, Zhou FC: Alcohol teratogenesis: mechanisms of damage and strategies for intervention. Exp Biol Med (Maywood) 2005;230:394-406.
13.
Rubert G, Minana R, Pascual M, Guerri C: Ethanol exposure during embryogenesis decreases the radial glial progenitorpool and affects the generation of neurons and astrocytes. J Neurosci Res 2006;84:483-496.
14.
Canales JJ: Comparative neuroscience of stimulant-induced memory dysfunction: role for neurogenesis in the adult hippocampus. Behav Pharmacol 2010;21:379-393.
15.
Canales JJ: Deficient plasticity in the hippocampus and the spiral of addiction: focus on adult neurogenesis. Curr Top Behav Neurosci 2013;5:293-312.
16.
Cho KO, Rhee GS, Kwack SJ, Chung SY, Kim SY: Developmental exposure to 3,4-methylenedioxymethamphetamine results in downregulation of neurogenesis in the adult mouse hippocampus. Neuroscience 2008;154:1034-1041.
17.
Redila VA, Olson AK, Swann SE, Mohades G, Webber AJ, Weinberg J, Christie BR: Hippocampal cell proliferation is reduced following prenatal ethanol exposure but can be rescued with voluntary exercise. Hippocampus 2006;16:305-311.
18.
Zimmerberg B, Sukel HL, Stekler JD: Spatial learning of adult rats with fetal alcohol exposure: deficits are sex-dependent. Behav Brain Res 1991;42:49-56.
19.
Battaglia G, Cabrera TM, Van de Kar LD: Prenatal cocaine produces biochemical and functional changes in brain serotonin systems in rat progeny. NIDA Res Monogr 1995;158:115-148.
20.
Clancy B, Finlay BL, Darlington RB, Anand KJ: Extrapolating brain development from experimental species to humans. Neurotoxicology 2007;28:931-937.
21.
Orr TE, Whitford-Stoddard JL, Elkins RL: Taste-aversion-prone (TAP) rats and taste-aversion-resistant (TAR) rats differ in ethanol self-administration, but not in ethanol clearance or general consumption. Alcohol 2004;33:1-7.
22.
Maxwell CR, Spangenberg RJ, Hoek JB, Silberstein SD, Oshinsky ML: Acetate causes alcohol hangover headache in rats. PLoS One 2010;5:e15963.
23.
Driscoll CD, Streissguth AP, Riley EP: Prenatal alcohol exposure: comparability of effects in humans and animal models. Neurotoxicol Teratol 1990;12:231-237.
24.
Adori C, Zelena D, Timar J, Gyarmati Z, Domokos A, Sobor M, Furst Z, Makara G, Bagdy G: Intermittent prenatal MDMA exposure alters physiological but not mood related parameters in adult rat offspring. Behav Brain Res 2010;206:299-309.
25.
Ferragud A, Velazquez-Sanchez C, Hernandez-Rabaza V, Nacher A, Merino V, Carda M, Murga J, Canales JJ: A dopamine transport inhibitor with markedly low abuse liability suppresses cocaine self-administration in the rat. Psychopharmacology (Berl) 2009;207:281-289.
26.
Dominguez-Escriba L, Hernandez-Rabaza V, Soriano-Navarro M, Barcia JA, Romero FJ, Garcia-Verdugo JM, Canales JJ: Chronic cocaine exposure impairs progenitor proliferation but spares survival and maturation of neural precursors in adult rat dentate gyrus. Eur J Neurosci 2006;24:586-594.
27.
Lazic SE, Essioux L: Improving basic and translational science by accounting for litter-to-litter variation in animal models. BMC Neurosci 2013;14:37.
28.
Sutherland RJ, McDonald RJ, Savage DD: Prenatal exposure to moderate levels of ethanol can have long-lasting effects on hippocampal synaptic plasticity in adult offspring. Hippocampus 1997;7:232-238.
29.
Frederick AL, Stanwood GD: Drugs, biogenic amine targets and the developing brain. Dev Neurosci 2009;31:7-22.
30.
Swartzwelder HS, Farr KL, Wilson WA, Savage DD: Prenatal exposure to ethanol decreases physiological plasticity in the hippocampus of the adult rat. Alcohol 1988;5:121-124.
31.
Minetti A, Arolfo MP, Virgolini MB, Brioni JD, Fulginiti S: Spatial learning in rats exposed to acute ethanol intoxication on gestational day 8. Pharmacol Biochem Behav 1996;53:361-367.
32.
Reyes E, Wolfe J, Savage DD: The effects of prenatal alcohol exposure on radial arm maze performance in adult rats. Physiol Behav 1989;46:45-48.
33.
Aimone JB, Deng W, Gage FH: Adult neurogenesis: integrating theories and separating functions. Trends Cogn Sci 2010;14:325-337.
34.
Wojtowicz JM: Adult neurogenesis. From circuits to models. Behav Brain Res 2012;227:490-496.
35.
Canales JJ: Adult neurogenesis and the memories of drug addiction. Eur Arch Psychiatry Clin Neurosci 2007;257:261-270.
36.
Eisch AJ, Harburg GC: Opiates, psychostimulants, and adult hippocampal neurogenesis: insights for addiction and stem cell biology. Hippocampus 2006;16:271-286.
37.
Nixon K, Crews FT: Binge ethanol exposure decreases neurogenesis in adult rat hippocampus. J Neurochem 2002;83:1087-1093.
38.
Hernandez-Rabaza V, Dominguez-Escriba L, Barcia JA, Rosel JF, Romero FJ, Garcia-Verdugo JM, Canales JJ: Binge administration of 3,4-methylenedioxymethamphetamine (‘ecstasy') impairs the survival of neural precursors in adult rat dentate gyrus. Neuropharmacology 2006;51:967-973.
39.
Reagan-Shaw S, Nihal M, Ahmad N: Dose translation from animal to human studies revisited. FASEB J 2008;22:659-661.
40.
Gil-Mohapel J, Boehme F, Kainer L, Christie BR: Hippocampal cell loss and neurogenesis after fetal alcohol exposure: insights from different rodent models. Brain Res Rev 2010;64:283-303.
41.
Gil-Mohapel J, Boehme F, Patten A, Cox A, Kainer L, Giles E, Brocardo PS, Christie BR: Altered adult hippocampal neuronal maturation in a rat model of fetal alcohol syndrome. Brain Res 2011;1384:29-41.
42.
Choi IY, Allan AM, Cunningham LA: Moderate fetal alcohol exposure impairs the neurogenic response to an enriched environment in adult mice. Alcohol Clin Exp Res 2005;29:2053-2062.
43.
Uban KA, Sliwowska JH, Lieblich S, Ellis LA, Yu WK, Weinberg J, Galea LA: Prenatal alcohol exposure reduces the proportion of newly produced neurons and glia in the dentate gyrus of the hippocampus in female rats. Horm Behav 2010;58:835-843.
44.
Thompson VB, Heiman J, Chambers JB, Benoit SC, Buesing WR, Norman MK, Norman AB, Lipton JW: Long-term behavioral consequences of prenatal MDMA exposure. Physiol Behav 2009;96:593-601.
45.
Berman RF, Hannigan JH: Effects of prenatal alcohol exposure on the hippocampus: spatial behavior, electrophysiology, and neuroanatomy. Hippocampus 2000;10:94-110.
46.
Mohamed WM, Hamida SB, de Vasconcelos AP, Cassel JC, Jones BC: Interactions between 3,4-methylenedioxymethamphetamine and ethanol in humans and rodents. Neuropsychobiology 2009;60:188-194.
47.
Hamida SB, Tracqui A, de Vasconcelos AP, Szwarc E, Lazarus C, Kelche C, Jones BC, Cassel JC: Ethanol increases the distribution of MDMA to the rat brain: possible implications in the ethanol-induced potentiation of the psychostimulant effects of MDMA. Int J Neuropsychopharmacol 2009;12:749-759.
48.
Upreti VV, Eddington ND, Moon KH, Song BJ, Lee IJ: Drug interaction between ethanol and 3,4-methylenedioxymethamphetamine (‘ecstasy'). Toxicol Lett 2009;188:167-172.
49.
Hipolito L, Sanchez MJ, Polache A, Granero L: Brain metabolism of ethanol and alcoholism: an update. Curr Drug Metab 2007;8:716-727.
50.
Niemelä O: Acetaldehyde adducts in circulation. Novartis Found Symp 2007;285:183-192.
Copyright / Drug Dosage / Disclaimer
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.
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 government 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.
You do not currently have access to this content.