Effect of MDMA exposure during pregnancy on cell apoptosis, astroglia, and microglia activity in rat offspring striatum

Document Type : Original Article


1 Department of Biology, Faculty of Basic Sciences, Golestan University, Gorgan, Iran

2 Department of Biology, Faculty of Basic Sciences, Yasuj University, Yasuj, Iran

3 Gorgan Congenital Malformations Research Center, Golestan University of Medical Sciences, Gorgan, Iran



Objective(s): Ecstasy is a popular recreational psychostimulant with side effects on the central nervous system. This study examined the corpus striatum tissue of adult rats that received ecstasy during the embryonic period for histological and molecular studies.
Materials and Methods: Rats were divided into control and ecstasy groups. The ecstasy group was given MDMA 15 mg/kg intraperitoneally twice daily at 8-hour intervals on days 7–15 of gestation. At the age of 15 weeks, adult offspring of both groups were examined for learning and memory study by the Morris water maze test. Then, ventral striatum tissue was harvested for TUNEL assay, Nissl staining, and real-time PCR for the expression of the GFAP and CD11b. 
Results: Ecstasy up-regulated the GFAP and CD11b expression in the striatum of offspring (*P˂0.05). Furthermore, the Morris water maze test showed that exposure to ecstasy significantly impaired learning and spatial memory (*P˂0.05). TUNEL assay results did not show any significant change in the number of apoptotic cells in the striatum tissue of ecstasy offspring compared with controls, while Nissl staining showed a significant decrease in the number of neurons in the ecstasy group (*P˂0.05).
Conclusion: Exposure to ecstasy during pregnancy causes long-lasting changes in brain regions underlying learning and memory, including the striatum, and impaired working memory in the offspring. In addition, these data provide the first evidence that exposure to ecstasy during the embryonic period causes a persistent change in the activity of microglial cells and the number of astrocyte cells in the striatum.


1. Simantov R. Multiple molecular and neuropharmacological effects of MDMA (Ecstasy). Life Sci 2004; 74:803-814.
2. Costa G, De Luca MA, Piras G, Marongiu J, Fattore L, Simola N. Neuronal and peripheral damages induced by synthetic psychoactive substances: An update of recent findings from human and animal studies. Neural Regen Res 2020; 15:802-816.
3. Plummer CM, Breadon TW, Pearson JR, Jones OA. The synthesis and characterisation of MDMA derived from a catalytic oxidation of material isolated from black pepper reveals potential route specific impurities. Sci Justice 2016; 56:223-230.
4. Mustafa NS, Bakar NHA, Mohamad N, Adnan LHM, Fauzi NFAM, Thoarlim A, et al. MDMA and the Brain: A short review on the role of neurotransmitters in neurotoxicity. Basic Clin Neurosci 2020; 11:381-387.
5. Green AR, Mechan AO, Elliott JM, O’Shea E, Colado MI. The pharmacology and clinical pharmacology of 3, 4-methylenedioxymethamphetamine (MDMA,“ecstasy”). Pharmacol Rev 2003; 55:463-508.
6. Blagrove M, Seddon J, George S, Parrott AC, Stickgold R, Walker MP, et al. Procedural and declarative memory task performance, and the memory consolidation function of sleep, in recent and abstinent ecstasy/MDMA users. J Psychopharmacol 2011; 25:477-465.
7. Hall A, Henry J. Acute toxic effects of ‘Ecstasy’(MDMA) and related compounds: overview of pathophysiology and clinical management. Br J Anaesth 2006; 96:678-685.
8. Bradbury S. The role of serotonin in MDMA self-administration in rats.  2014.
9. Jahanshahi M, Haidari K, Mahaki-Zadeh S, Nikmahzar E, Babakordi F. Effects of repeated administration of 3, 4-methylenedioxymethamphetamine (MDMA) on avoidance memory and cell density in rats’ hippocampus. Basic Clin Neurosci 2013; 4:57-63.
10. Moratalla R, Khairnar A, Simola N, Granado N, García-Montes JR, Porceddu PF, et al. Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms. Prog Neurobiol 2017; 155:149-170.
11. Collins SA, Gudelsky GA, Yamamoto BK. MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors. Eur J Pharmacol 2015; 761:95-100.
12. Commins D, Vosmer G, Virus R, Woolverton W, Schuster C, Seiden L. Biochemical and histological evidence that methylenedioxymethamphetamine (MDMA) is toxic to neurons in the rat brain. J Pharmacol Exp Ther 1987; 241:338-345.
13. Scallet A, Lipe G, Ali S, Holson R, Frith C, Slikker Jr W. Neuropathological evaluation by combined immunohistochemistry and degeneration-specific methods: application to methylenedioxymethamphetamine. Neurotoxicology 1988; 9:529-537.
14. Scheffel U, Szabo Z, Mathews WB, Finley PA, Dannals RF, Ravert HT, et al. In vivo detection of short and long‐ In vivo detection of short‐and long term MDMA neurotoxicity—a positron emission tomography study in the living baboon brain. Synapse 1998; 29:183-192.
15. Granado N, O’Shea E, Bove J, Vila M, Colado MI, Moratalla R. Persistent MDMA‐induced dopaminergic neurotoxicity in the striatum and substantia nigra of mice. J Neurochem 2008; 107:1102-1112.
16. Sarkar S, Schmued L. Neurotoxicity of ecstasy (MDMA): An overview. Curr Pharm Biotechnol 2010; 11:460-469.
17. Morelli M and Costa G. MDMA administration during adolescence exacerbates MPTP-induced cognitive impairment and neuroinflammation in the hippocampus and prefrontal cortex. Psychopharmacology 2014; 231:4007-4018.
18. Ahmad MA, Kareem O, Khushtar M, Akbar M, Haque MR, Iqubal A, et al. Neuroinflammation: A Potential Risk for Dementia. Int J Mol Sci 2022; 23:616-633.
19. Brambilla R. Neuroinflammation, the thread connecting neurological disease. Acta Neuropathol 2019; 137:689-691.
20. Kitamura O, Takeichi T, Wang EL, Tokunaga I, Ishigami A, Kubo S-i. Microglial and astrocytic changes in the striatum of methamphetamine abusers. Leg Med 2010; 12:57-62.
21. Green AR, Gabrielsson J, Marsden CA, Fone KC. MDMA: on the translation from rodent to human dosing. Psychopharmacology 2009; 204:375-378.
22. Teixeira-Gomes A, Costa VM, Feio-Azevedo R, Duarte JA, Duarte-Araújo M, Fernandes E, et al. “Ecstasy” toxicity to adolescent rats following an acute low binge dose. BMC Pharmacol Toxicol 2016; 17:1-14.
23. Koprich JB, Chen E-Y, 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.
24. Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 1984; 11:47-60.
25. Bahrehbar K, Valojerdi MR, Esfandiari F, Fathi R, Hassani S-N, Baharvand H. Human embryonic stem cell-derived mesenchymal stem cells improved premature ovarian failure. World J Stem Cells 2020; 12:1-21.
26. Bahrehbar K, Malakhond MK, Gholami S. Tracking of human embryonic stem cell derived mesenchymal stem cells in premature ovarian failure model mice. Biochem Biophys Res Commun 2021; 577:6-11.
27. Lyles J, Cadet JL. Methylenedioxymethamphetamine (MDMA, Ecstasy) neurotoxicity: Cellular and molecular mechanisms. Brain Res Rev 2003; 42:155-168.
28. Iqubal A, Haque SE, Sharma S, Ansari MA, Khan V, Iqubal MK. Clinical updates on drug-induced cardiotoxicity. Int J Pharm Sci Res 2018; 9:16-26.
29. Ritzel RM, Patel AR, Pan S, Crapser J, Hammond M, Jellison E, et al. Age-and location-related changes in microglial function. Neurobiol Aging 2015; 36:2153-2163.
30. Mir RH, Shah AJ, Mohi-Ud-Din R, Pottoo FH, Dar M, Jachak SM, et al. Natural anti-compounds as drug. Curr Med Chem 2021; 28:4799-4825. 
31. Shabab T, Khanabdali R, Moghadamtousi SZ, Kadir HA, Mohan G. Neuroinflammation pathways: A general review. Int J Neurosci 2017; 127:624-633.
32. Jacque C, Vinner C, Kujas M. Racadot J, Baumann N. Determination of glial (GFAP) in human brain tumors. J Neurol Sci 1978; 35:147-155.
33. Hol EM, Pekny M. Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. Curr Opin Cell Biol 2015; 32:121-130.
34. Aguirre N, Barrionuevo M, Ramírez MJ, Del Río J, Lasheras B. α-Lipoic acid prevents 3, 4- methylenedioxy-methamphetamine (MDMA)-induced neurotoxicity. Neuroreport 1999; 10:3675-368.
35. Frau L, Simola N, Plumitallo A, Morelli M. Microglial and astroglial activation by 3, 4‐methylenedioxymethamphetamine (MDMA) in mice depends on S (+) enantiomer and is associated with motility. J Neurochem 2013; 124:69-78.
36. Block ML, Zecca L, Hong J-S. Microglia-mediated neurotoxicity: Uncovering the molecular an increase in body temperature and mechanisms. Nat Rev Neurosci 2007; 8:57-69.
37. Hooper C, Pocock JM. Chromogranin A activates diverse pathways mediating inducible nitric oxide expression and apoptosis in primary microglia. Neurosci Lett 2007; 413:227-232.
38. Squier M, Jalloh S, Hilton-Jones D, Series H. Death after ecstasy ingestion: Neuropathological findings. J Neurol Neurosurg Psychiatry 1995; 58:756.
39. Spatt J, Glawar B, Mamoli B. A pure amnestic syndrome after MDMA (“ ecstasy”) ingestion. J Neurol Neurosurg Psychiatry 1997; 62:418.-428.
40. Vorhees CV, Schaefer TL, Skelton MR, Grace CE. Herring NR, Williams MT. (+/–) 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. Dev Neurosci 2009; 31:107-120.