Behavioral and electrophysiological aspects of cognition in neonate rats lactated by morphine addicted mothers

Document Type: Original Article


Physiology Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran


Objective(s): In addition to genetic factors, environmental phenomena during postnatal age highly affect development and, in turn, function of the brain. The present work evaluates if morphine consumption during lactation period influences the spatial performances and synaptic plasticity in rats at neonatal period of age.
Materials and Methods: Three groups of mothers were subcutaneously administered by 5 (M5), 10 (M10) or 20 (M20) mg/kg morphine every 12 hours during the lactation period. At 45 days old, their offspring were introduced to Morris water maze for assessment of spatial learning and memory. Basic field excitatory post-synaptic potentials (fEPSPs) were recorded in the CA1 area of hippocampus and, then, long term potentiation (LTP) was induced by tetanic stimulation.
Results: We found that the M10 and M20 rats spent more time and traveled longer distance to find the hidden platform of maze when compared to the control animals (PConclusion: The present study provides behavioral and electrophysiological proofs for negative effect of morphine on the hippocampal-related function in the neonatally morphine-exposed rats.


Main Subjects

1. Kim J, Ham S, Hong H, Moon C, Im HI. Brain reward circuits in morphine addiction. Mol Cells 2016; 39:645-653.
2. Nestler EJ. Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2001; 2:119-128.
3. Thomas SA. Neuromodulatory signaling in hippocampus-dependent memory retrieval. Hippocampus 2015; 25:415-431.
4. Andersen N, Krauth N, Nabavi S. Hebbian plasticity in vivo: relevance and induction. Curr Opin Neurobiol 2017; 45:188-192.
5. Han H, Dong Z, Jia Y, Mao R, Zhou Q, Yang Y, et al. Opioid addiction and withdrawal differentially drive long-term depression of inhibitory synaptic transmission in the hippocampus. Sci Rep 2015; 5:9666.
6. Drake CT, Milner TA. Mu opioid receptors are in discrete hippocampal interneuron subpopulations. Hippocampus 2002; 12:119-136.
7. Bao G, Kang L, Li H, Li Y, Pu L, Xia P, et al. Morphine and heroin differentially modulate in vivo hippocampal LTP in opiate-dependent rat. Neuropsychopharmacology 2007; 32:1738-1749.
8. Zhou M, Luo P, Lu Y, Li C-j, Wang D-s, Lu Q, et al. Imbalance of HCN1 and HCN2 expression in hippocampal CA1 area impairs spatial learning and memory in rats with chronic morphine exposure. Prog Neuropsychopharmacol Biol Psychiatry. 2015;56:207-214.
9. Miladi-Gorji H, Rashidy-Pour A, Fathollahi Y, Semnanian S, Jadidi M. Effects of voluntary exercise on hippocampal long-term potentiation in morphine-dependent rats. Neuroscience 2014; 256:83-90.
10. Lu G, Zhou QX, Kang S, Li QL, Zhao LC, Chen JD, et al. Chronic morphine treatment impaired hippocampal long-term potentiation and spatial memory via accumulation of extracellular adenosine acting on adenosine A1 receptors. J Neurosci 2010; 30:5058-5070.
11. Nasiraei-Moghadam S, Sherafat MA, Safari MS, Moradi F, Ahmadiani A, Dargahi L. Reversal of prenatal morphine exposure-induced memory deficit in male but not female rats. J Mol Neurosci 2013; 50:58-69.
12. Morishita H, Hensch TK. Critical period revisited: impact on vision. Curr Opi Neurobiol 2008; 18:101-107.
13. Blair MG, Nguyen NN, Albani SH, L’Etoile MM, Andrawis MM, Owen LM, et al. Developmental changes in structural and functional properties of hippocampal AMPARs parallels the emergence of deliberative spatial navigation in juvenile rats. J Neurosci 2013; 33:12218-12228.
14. Fodor A, Timar J, Dora Z. Behavioral effects of perinatal opioid exposure. 2014. p. 1-8.
15. Rozisky JR, Laste G, de Macedo IC, Santos VS, Krolow R, Noschang C, et al. Neonatal morphine administration leads to changes in hippocampal bdnf levels and antioxidant enzyme activity in the adult life of rats. Neurochem Res 2013; 38:494-503.
16. Yang SN, Huang LT, Wang CL, Chen WF, Yang CH, Lin SZ, et al. Prenatal administration of morphine decreases CREBSerine-133 phosphorylation and synaptic plasticity range mediated by glutamatergic transmission in the hippocampal CA1 area of cognitive-deficient rat offspring. Hippocampus 2003; 13:915-921.
17. Tao P-L, Yeh G-C, Su C-H, Wu Y-H. Co-administration of dextromethorphan during pregnancy and throughout lactation significantly decreases the adverse effects associated with chronic morphine administration in rat offspring. Life Sci 2001; 69:2439-2450.
18. Yeh GC, Chen CH, Tao PL. Pre- and post-natal exposure to morphine induces an alteration in the developmental expression of the N-Methyl-D-Aspartate receptor in neonatal rat brain. Analgesia 1995; 1.
19. Yang SN, Liu CA, Chung MY, Huang HC, Yeh GC, Wong CS, et al. Alterations of postsynaptic density proteins in the hippocampus of rat offspring from the morphine-addicted mother: Beneficial effect of dextromethorphan. Hippocampus 2006; 16:521-530.
20. Yang SN, Yang JM, Wu JN, Kao YH, Hsieh WY, Chao CC, et al. Prenatal exposure to morphine alters kinetic properties of NMDA receptor-mediated synaptic currents in the hippocampus of rat offspring. Hippocampus 2000; 10:654-662.
21. Miladi-Gorji H, Rashidy-Pour A, Fathollahi Y, Akhavan MM, Semnanian S, Safari M. Voluntary exercise ameliorates cognitive deficits in morphine dependent rats: the role of hippocampal brain-derived neurotrophic factor. Neurobiol Learn Mem 2011; 96:479-491.
22. Calabrese E, Badea A, Watson C, Johnson GA. A quantitative magnetic resonance histology atlas of postnatal rat brain development with regional estimates of growth and variability. NeuroImage 2013; 71:196-206.
23. Yang L, Pan Z, Zhou L, Lin S, Wu K. Continuously changed genes during postnatal periods in rat visual cortex. Neurosci Lett 2009; 462:162-165.
24. Taghizadeh M, Talaei SA, Salami M. Vitamin D deficiency impairs spatial learning in adult rats. Iran Biomed J 2013; 17:42-48.
25. Talaei SA, Azami A, Salami M. Postnatal development and sensory experience synergistically underlie the excitatory/inhibitory features of hippocampal neural circuits: glutamatergic and GABAergic neurotransmission. Neuroscience 2016; 318:230-243.
26. Feilberg VL, Rosenborg D, Broen Christensen C, Mogensen JV. Excretion of morphine in human breast milk. Acta Anaesthesiol Scand 1989; 33:426-428.
27. Robieux I, Koren G, Vandenbergh H, Schneiderman J. Morphine excretion in breast milk and resultant exposure of a nursing infant. J Toxicol Clin Toxicol 1990; 28:365-370.
28. Zagon IS, McLaughlin PJ. Perinatal exposure to methadone alters sensitivity to drugs in adult rats. Neurobehav Toxicol Teratol 1984; 6:319-323.
29. Molnar E. Long-term potentiation in cultured hippocampal neurons. Semin Cell Dev Biol 2011; 22:506-513.
30. Okada T, Yamada N, Tsuzuki K, Horikawa HP, Tanaka K, Ozawa S. Long-term potentiation in the hippocampal CA1 area and dentate gyrus plays different roles in spatial learning. Eur J Neurosci 2003; 17:341-349.
31. Tao PL, Chen CF, Huang EY. Dextromethorphan attenuated the higher vulnerability to inflammatory thermal hyperalgesia caused by prenatal morphine exposure in rat offspring. J Biomed Sci 2011; 18:1423-0127.
32. Ghafari S, Golalipour MJ. Prenatal morphine exposure reduces pyramidal neurons in CA1, CA2 and CA3 subfields of mice hippocampus. Iran J Basic Med Sci 2014; 17:155-161.
33. Ahmadalipour A, Sadeghzadeh J, Vafaei AA, Bandegi AR, Mohammadkhani R, Rashidy-Pour A. Effects of environmental enrichment on behavioral deficits and alterations in hippocampal BDNF induced by prenatal exposure to morphine in juvenile rats. Neuroscience 2015;305:372-383.
34. Zarrinkalam E, Heidarianpour A, Salehi I, Ranjbar K, Komaki A. Effects of endurance, resistance, and concurrent exercise on learning and memory after morphine withdrawal in rats. Life Sci 2016; 157:19-24.
35. Ukai M, Watanabe Y, Kameyama T. Effects of endomorphins-1 and -2, endogenous mu-opioid receptor agonists, on spontaneous alternation performance in mice. Eur J Pharmacol 2000; 395:211-215.