Anatomical Science International

, Volume 93, Issue 3, pp 351–363 | Cite as

The effect of methamphetamine exposure during pregnancy and lactation on hippocampal doublecortin expression, learning and memory of rat offspring

  • Zahra Jalayeri-Darbandi
  • Aliakbar Rajabzadeh
  • Mahmoud Hosseini
  • Farimah Beheshti
  • Alireza Ebrahimzadeh-bideskan
Original Article


The aim of this study was to evaluate the effect of methamphetamine (MA) exposure during pregnancy and lactation on doublecortin (DCX) expression in the hippocampus of rat offspring and also on learning/memory. Thirty-five pregnant Wistar rats were randomly divided into seven groups of 5 rats each: three experimental groups, each receiving 5 mg/kg body weight (BW) intraperitoneal (i.p.) injections of MA during pregnancy or/and lactation; three sham groups, each receiving saline injections; one control group, receiving no injection. After the interventions, two male pups (1 and 22 days old) were randomly selected from each mother, sacrificed and their brains subjected to DCX immunohistochemistry. One additional male pup from each mother was randomly selected and maintained for 60 days for testing in the Morris water maze and passive avoidance tests. MA administration during pregnancy was found to have significantly decreased the number of DCX-positive cells in the CA1, CA3 and DG regions of the hippocampus in the 1-day pups (P ≤ 0.05) and to have significantly decreased the number of DCX-positive cells in only two regions of the hippocampus, the CA1 and DG regions, in 22-day old pups. In comparison, exposure to MA during lactation was only associated with a significant decrease in the number of DCX-positive cells in the DG. Exposure to MA during pregnancy had significant impact on the intensity of DCX expression in the hippocampus of 1- and 22-day pups (P ≤ 0.05). There was no significant difference in memory/learning among the study groups. Our results indicate the administration of MA during pregnancy had a greater effect that during the lactation period on DCX expression in the hippocampus of rat offspring.


Doublecortin Hippocampus Lactation Learning Memory Methamphetamine Pregnancy 



This article was derived from an MSc thesis and was financially supported by the Deputy of Research, Mashhad University of Medical Sciences, Mashhad, Iran (Code: 931789). We would like to thank Dr. Sokhtanloo for providing the methamphetamine and Ms Fatemeh Motejaded for her technical assistance.

Compliance and ethical standards

Conflict of interest

The authors declare that there is no any conflict of interest.


  1. Acuff-Smith KD, Schilling MA, Fisher JE, Vorhees CV (1996) Stage-specific effects of prenatal d-methamphetamine exposure on behavioral and eye development in rats. Neurotoxicol Teratol 18(2):199–215CrossRefPubMedGoogle Scholar
  2. Baei F, Rajabzadeh A, Bagheri J, Jalayeri Z, Ebrahimzadeh-Bideskan A (2017) Effect of methamphetamine exposure during pregnancy and lactation on polysialic acid-neural cell adhesion molecule expression in rat's offspring hippocampus. Metab Brain Dis 32(4):991–1002CrossRefPubMedGoogle Scholar
  3. Bagheri J, Rajabzadeh A, Baei F, Jalayeri Z, Ebrahimzadeh-bideskan A (2017) The effect of maternal exposure to methamphetamine during pregnancy and lactation period on hippocampal neurons apoptosis in rat offspring. Toxin Rev 36(3):1–10CrossRefGoogle Scholar
  4. Baptista S (2015) Impact of methamphetamine on dentate gyrus neurogenesis: the underlying mechanisms and the role of neuropeptide Y.
  5. Baptista S et al (2012) Neuropeptide Y promotes neurogenesis and protection against methamphetamine-induced toxicity in mouse dentate gyrus-derived neurosphere cultures. Neuropharmacology 62(7):2413–2423CrossRefPubMedGoogle Scholar
  6. Baptista S et al (2014) Methamphetamine decreases dentate gyrus stem cell self-renewal and shifts the differentiation towards neuronal fate. Stem Cell Res 13(2):329–341CrossRefPubMedGoogle Scholar
  7. Behnke M et al (2013) Prenatal substance abuse: short-and long-term effects on the exposed fetus. Pediatrics 131(3):e1009–e1024CrossRefPubMedGoogle Scholar
  8. Cao G et al (2013) Distinct roles of methamphetamine in modulating spatial memory consolidation, retrieval, reconsolidation and the accompanying changes of ERK and CREB activation in hippocampus and prefrontal cortex. Neuropharmacology 67:144–154CrossRefPubMedGoogle Scholar
  9. Chou Y-H et al (2007) Dopamine transporters and cognitive function in methamphetamine abuser after a short abstinence: a SPECT study. Eur Neuropsychopharmacol 17(1):46–52CrossRefPubMedGoogle Scholar
  10. Deng W et al (2009) Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain. J Neurosci 29(43):13532–13542CrossRefPubMedPubMedCentralGoogle Scholar
  11. Eghtedari A, Shariat V, Farahani H (2012) The comparison of cognitive functions in patients with methamphetamine induced psychosis and control group. Adv Cogn Sci 13(4):20Google Scholar
  12. Elibol-Can B et al (2014) Examination of Age-dependent effects of fetal ethanol exposure on behavior, hippocampal cell counts, and doublecortin immunoreactivity in rats. Dev Neurobiol 74(5):498–513CrossRefPubMedGoogle Scholar
  13. Francis F et al (1999) Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons. Neuron 23(2):247–256CrossRefPubMedGoogle Scholar
  14. Gao X et al (2011) Effects of developmental exposure to TiO2 nanoparticles on synaptic plasticity in hippocampal dentate gyrus area: an in vivo study in anesthetized rats. Biol Trace Elem Res 143(3):1616–1628CrossRefPubMedGoogle Scholar
  15. Gleeson JG et al (1999) Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 23(2):257–271CrossRefPubMedGoogle Scholar
  16. Hildebrandt K, Teuchert-Noodt G, Dawirs R (1999) A single neonatal dose of methamphetamine suppresses dentate granule cell proliferation in adult gerbils which is restored to control values by acute doses of haloperidol. J Neural Transm 106(5):549–558CrossRefPubMedGoogle Scholar
  17. Hosseini M et al (2010) The beneficial effects of olibanum on memory deficit induced by hypothyroidism in adult rats tested in Morris water maze. Arch Pharmacal Res 33(3):463–468CrossRefGoogle Scholar
  18. Hosseini M et al (2011) Inducible nitric oxide synthase inhibitor aminoguanidine, differently affects Morris water maze tasks of ovariectomized and naive female rats. Acta Physiol Hung 98(4):421–432CrossRefPubMedGoogle Scholar
  19. Hrubá L et al (2009) Does cross-fostering modify the prenatal effect of methamphetamine on learning of adult male rats. Prague Med Rep 110:191–200PubMedGoogle Scholar
  20. Ijomone OM et al (2011) Effects of methamphetamine on the hippocampus of rats: behavioural and morphological approach. J Neurosci Behav Health 3(8):107–112Google Scholar
  21. Klempin F et al (2011) Properties of doublecortin-(DCX)-expressing cells in the piriform cortex compared to the neurogenic dentate gyrus of adult mice. PLoS One 6(10):e25760CrossRefPubMedPubMedCentralGoogle Scholar
  22. Kochman LJ, Fornal CA, Jacobs BL (2009) Suppression of hippocampal cell proliferation by short-term stimulant drug administration in adult rats. Eur J Neurosci 29(11):2157–2165CrossRefPubMedPubMedCentralGoogle Scholar
  23. Kwiatkowski MA et al (2014) Effects of prenatal methamphetamine exposure: a review of cognitive and neuroimaging studies. Metab Brain Dis 29(2):245–254CrossRefPubMedGoogle Scholar
  24. Macúchová E, Nohejlová-Deykun K, Slamberova R (2013) Effect of methamphetamine on cognitive functions of adult female rats prenatally exposed to the same drug. Physiol Res 62 (Suppl. 1):S89–S98PubMedGoogle Scholar
  25. Mandyam CD et al (2008) Varied access to intravenous methamphetamine self-administration differentially alters adult hippocampal neurogenesis. Biol Psychiatry 64(11):958–965CrossRefPubMedPubMedCentralGoogle Scholar
  26. McDonnell-Dowling K, Kelly JP (2016) Does route of methamphetamine exposure during pregnancy have an impact on neonatal development and behaviour in rat offspring? Int J Dev Neurosci 49:14–22CrossRefPubMedGoogle Scholar
  27. Moenk MD, Matuszewich L (2012) Juvenile but not adult methamphetamine exposure improves performance in the Morris Water Maze in male rats. Int J Dev Neurosci 30(4):325–331CrossRefPubMedGoogle Scholar
  28. Mohammadipour A et al (2014) Maternal exposure to titanium dioxide nanoparticles during pregnancy; impaired memory and decreased hippocampal cell proliferation in rat offspring. Environ Toxicol Pharmacol 37(2):617–625CrossRefPubMedGoogle Scholar
  29. Moszczynska A et al (2015) Neurotoxic methamphetamine doses increase LINE-1 expression in the neurogenic zones of the adult rat brain. Sci Rep 5:1–14CrossRefGoogle Scholar
  30. Pourmotabbed A et al (2011) Effect of prenatal pentylenetetrazol-induced kindling on learning and memory of male offspring. Neuroscience 172:205–211CrossRefPubMedGoogle Scholar
  31. Rajabzadeh AA, Ebrahimzadeh-Bideskan AR, Haghir H, Fazel AR (2011) Morphometrical study of polysialylated neural cell adhesion molecule positive cells in rat pups hippocampus following induction of seizure during pregnancy. Iran Biomed J 15(4):157–163PubMedPubMedCentralGoogle Scholar
  32. Rajabzadeh A, Ebrahimzadeh-Bideskan AR, Fazel A, Sankian M, Rafatpanah H, Haghir H (2012) The effect of PTZ-induced epileptic seizures on hippocampal expression of PSA-NCAM in offspring born to kindled rats. J Biomed Sci 19(1):1–9CrossRefGoogle Scholar
  33. Rambousek L et al (2014) Sex differences in methamphetamine pharmacokinetics in adult rats and its transfer to pups through the placental membrane and breast milk. Drug Alcohol Depend 139:138–144CrossRefPubMedGoogle Scholar
  34. Recinto P et al (2012) Levels of neural progenitors in the hippocampus predict memory impairment and relapse to drug seeking as a function of excessive methamphetamine self-administration. Neuropsychopharmacology 37(5):1275–1287CrossRefPubMedGoogle Scholar
  35. Schutová B et al (2008) Impact of methamphetamine administered prenatally and in adulthood on cognitive functions of male rats tested in Morris water maze. Prague Med Rep 109(1):62–70PubMedGoogle Scholar
  36. Smith AM, Chen W-JA (2009) Neonatal amphetamine exposure and hippocampus-mediated behaviors. Neurobiol Learn Mem 91(3):207–217CrossRefPubMedPubMedCentralGoogle Scholar
  37. Smith L et al (2003) Effects of prenatal methamphetamine exposure on fetal growth and drug withdrawal symptoms in infants born at term. J Dev Behav Pediatr 24(1):17–23CrossRefPubMedGoogle Scholar
  38. Thompson PM et al (2004) Structural abnormalities in the brains of human subjects who use methamphetamine. J Neurosci 24(26):6028–6036CrossRefPubMedGoogle Scholar
  39. Tian C, Murrin LC, Zheng JC (2009) Mitochondrial fragmentation is involved in methamphetamine induced cell death in rat hippocampal neural progenitor cells. PloS one 4(5):1–12CrossRefGoogle Scholar
  40. Turowski P, Kenny B-A (2015) The blood-brain barrier and methamphetamine: open sesame? Front Neurosci 9:156CrossRefPubMedPubMedCentralGoogle Scholar
  41. Venkatesan A, Uzasci L, Chen Z, Rajbhandari L, Anderson C, Lee MH, Bianchet MA, Cotter R, Song H, Nath A (2011) Impairment of adult hippocampal neural progenitor proliferation by methamphetamine: role for nitrotyrosination. Mol Brain 4:28CrossRefPubMedPubMedCentralGoogle Scholar
  42. Walker TL et al (2007) The doublecortin-expressing population in the developing and adult brain contains multipotential precursors in addition to neuronal-lineage cells. J Neurosci 27(14):3734–3742CrossRefPubMedGoogle Scholar
  43. Williams MT et al (2003) Developmental d-methamphetamine treatment selectively induces spatial navigation impairments in reference memory in the Morris water maze while sparing working memory. Synapse 48(3):138–148CrossRefPubMedGoogle Scholar
  44. Yuan CJ et al (2011) Extended access methamphetamine decreases immature neurons in the hippocampus which results from loss and altered development of neural progenitors without altered dynamics of the S-phase of the cell cycle. Pharmacol Biochem Behav 100(1):98–108CrossRefPubMedPubMedCentralGoogle Scholar
  45. Zhang J, Jiao J (2015) Molecular biomarkers for embryonic and adult neural stem cell and neurogenesis. BioMed Res Int 2015:727542PubMedPubMedCentralGoogle Scholar

Copyright information

© Japanese Association of Anatomists 2017

Authors and Affiliations

  • Zahra Jalayeri-Darbandi
    • 1
  • Aliakbar Rajabzadeh
    • 1
    • 2
  • Mahmoud Hosseini
    • 3
  • Farimah Beheshti
    • 4
  • Alireza Ebrahimzadeh-bideskan
    • 1
    • 2
  1. 1.Department of Anatomy and Cell Biology, School of MedicineMashhad University of Medical SciencesMashhadIran
  2. 2.Microanatomy Research CentreMashhad University of Medical SciencesMashhadIran
  3. 3.Physiology, Neurocognitive Research Centre, School of MedicineMashhad University of Medical SciencesMashhadIran
  4. 4.Department of Physiology, School of MedicineMashhad University of Medical SciencesMashhadIran

Personalised recommendations