Effect of Restraint Stress during Gestation on Pentylenetetrazol-Induced Epileptic Behaviors in Rat Offspring

Document Type: Original Article


1 Department of Physiology, Medical Faculty, Urmia University of Medical Science, Urmia, Iran

2 Department of Physiology, Neurophysiology Research Center, Urmia University of Medical Science, Urmia, Iran



Epilepsy is a neurodevelopmental disorder which is strongly influenced by genetic and environmental factors. Gestational stress has been shown to be an important factor for affecting seizure susceptibility. The present study was conducted to address whether gestational stress may affect pentylentetrazol (PTZ)-induced epileptic behavior in rat offspring in a sex- and age- dependent manner.
Materials and Methods:
Pregnant rats were divided into control and stressed groups (n=6 in each). In the stressed group, pregnant rats were under restraint stress and held immobile in the Plexiglas tube twice per day one hour per session for three consecutive days started on day 17 of pregnancy. To induce seizure, on postnatal days 15 (P15) and 25 (P25), PTZ (40-50 mg/kg, IP) was injected to rat offspring (n=12, one male and one female from any litter for each group/day). Then, epileptic behaviors of each rat were recorded.
Epileptic behaviors of stressed pups showed significant changes in comparison to control ones. The time to onset of the first epileptic behavior was shortened while mean duration and frequency of tonic-clonic attacks increased in stressed pups on both P15 and P25. Female offspring were different from male offspring in terms of epileptic behavior. Moreover, focal attacks were more obvious and significantly longer in the offspring of stressed group at the age of 25 days than those of 15 day old.
Prenatal restraint stress potentiated PTZ-induced epileptic behavior, age and sex dependently, probably due to alteration of neural and endocrine pathways during developmental process. Male and younger rats were more sensitive to stress than female and older ones.


afterselective reduction of tonic inhibition in GABAA receptor alpha5 subunit-deficient mice. J Neurophysiol 2006; 95:2796-2807.

26. Mody IPR. Diversity of inhibitory neurotransmission through GABAA receptors. Trends Neurosci 2004; 27:569-575.

27. Szyndler J, Maciejak P, Turzynska D, Sobolewska A, Bidzinski A, Plaznik A. Time course of changes in the concentrations of monoamines in the brain structures of pentylenetetrazole-kindled rats. J Neural Transm 2010; 117:707-718.

28. Chadda R, Devaud LL. Sex differences in effects of mild chronic stress on seizure risk and GABAA receptors in rats. Pharmacol Biochem Behav 2004; 78:495-504.

29. Inan SY, Aksu F. Influence of sex on the interaction between dizocilpine (MK-801) pretreatment and acute cold-restraint stress in epilepsy susceptibility in an animal study. Gender Med 2008; 5:136-146.

30. Peternel S, Pilipovic K, Zupan G. Seizure susceptibility and the brain regional sensitivity to oxidative stress in male and female rats in the lithium-pilocarpine model of temporal lobe epilepsy. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:456-462.

31. Frye CA. Hormonal influences on seizures: basic neurobiology. Int Rev Neurobiol 2008; 83:27-77.

17. Brunson KL, Chen Y, Avishai-Eliner S, Baram TZ. Stress and the developing hippocampus: a double-edged sword? Mol Neurobiol 2003; 27:121-136.

18. Lemaire V, Koehl M, Le Moal M, Abrous DN. Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc Natl Acad Sci U S A 2000; 97:11032-11037.

19. Hosseini-Sharifabad M, Esfandiari E, Hosseini-Sharifabad A. The effect of prenatal exposure to restraint stress on hippocampal granule neurons of adult rat offspring. Iran J Basic Med Sci 2012; 15:1060-1067.

20. Avishai-Eliner S, Brunson KL, Sandman CA, Baram TZ. Stressed-out, or in (utero)? Trends Neurosci 2002; 25:518-524.

21. Jiong L, Jorn O, Carsten O, Jakob C, Dorthe H, Mogens V. Prenatal stress and risk of febrile seizures in children. J Autism Dev Disord 2009; 39:1047-1052.

22. Seckl JR. Prenatal glucocorticoids and long-term programming. Eur J Endocrinol 2004; 151 :U49-62.

23. Barrot M, Abrous DN, Marinelli M, Rouge-Pont F, Le Moal M, Piazza PV. Influence of glucocorticoids on dopaminergic transmission in the rat dorsolateral striatum. Eur J Neurosci 2001; 13:812-818.

24. Kapoor A, Dunn E, Kostaki A, Andrews MH, Matthews SG. Fetal programming of hypothalamo-pituitary-adrenal function: prenatal stress and glucocorticoids. J Physiol 2006; 572:31-44.

25. Glykys J MI. Hippocampal network hyperactivity after


1. Heinrichs SC. Neurobehavioral consequences of stressor exposure in rodent models of epilepsy. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:808-815.

2. Ahmadzadeh R, Saboory E, Roshan-Milani S, Pilehvarian AA. Predator and restraint stress during gestation facilitates pilocarpine-induced seizures in prepubertal rats. Dev Psychobiol 2011; 53:806-812.

3. Sadaghiani MM, Saboory E. Prenatal stress potentiates pilocarpine-induced epileptic behaviors in infant rats both time and sex dependently. Epilepsy Behav 2010; 18:166-170.

4. Christensen J, Li J, Vestergaard M, Olsen J. Stress and epilepsy: a population-based cohort study of epilepsy in parents who lost a child. Epilepsy Behav 2007; 11:324-328.

5. Reddy DS, Rogawski MA. Stress-induced deoxycorticosterone-derived neurosteroids modulate GABA(A) receptor function and seizure susceptibility. J Neurosci 2002; 22:3795-3805.

6. Hess CP, Barkovich AJ. Seizures: emergency neuroimaging. Neuroimaging Clin N Am 2010; 20:619-637.

7. Tolmacheva EA, Oitzl MS, van Luijtelaar G. Stress, glucocorticoids and absences in a genetic epilepsy model. Horm Behav 2012; 61:706-710.

8. Edwards HE, Dortok D, Tam J, Won D, Burnham WM. Prenatal stress alters seizure thresholds and the development of kindled seizures in infant and adult rats. Horm Behav 2002; 42:437-447.

9. Frye CA, Bayon LE. Prenatal stress reduces the effectiveness of the neurosteroid 3 alpha,5 alpha-THP to block kainic-acid-induced seizures. Dev Psychobiol 1999; 34:227-234.

10. Weinstock M. The long-term behavioural consequences of prenatal stress. Neurosci Biobehav Rev 2008; 32:1073-1086.

11. Sarkisian MR. Overview of the current animal Mmdels for human seizure and epileptic disorders. Epilepsy Behav 2001; 2:201-216.

12. De Lima TC, Rae GA. Effects of cold-restraint and swim stress on convulsions induced by pentylenetetrazol and electroshock: influence of naloxone pretreatment. Pharmacol Biochem Behav 1991; 40:297-300.

13. Meilleur S, Aznavour N, Descarries L, Carmant L, Mamer OA, Psarropoulou C. Pentylenetetrazol-induced seizures in immature rats provoke long-term changes in adult hippocampal cholinergic excitability. Epilepsia 2003; 44:507-517.

14. Heshmatian B, Roshan-Milani S, Saboory E. Prenatal acute stress attenuated epileptiform activities in neonate mice. Yakhteh Med J 2010; 12:81-86.

15. Itoh K, Watanabe M. Paradoxical facilitation of pentylenetetrazole-induced convulsion susceptibility in mice lacking neuronal nitric oxide synthase. Neuroscience 2009; 159:735-743.

16. Rangon CM, Fortes S, Lelievre V, Leroux P, Plaisant F, Joubert C, et al. Chronic mild stress during gestation worsens neonatal brain lesions in mice. J Neurosci 2007; 27:7532-7540