Abstract

Objective: Anxiety and depression are common comorbidities in patients with epilepsy. Sodium valproate is a long-established antiepileptic drug used for seizure control. The present study aimed to evaluate the effects of sodium valproate on anxiety-related behavior in genetically determined absence epileptic WAG/Rij rats using the open field test.

Materials and Methods: Twenty-eight WAG/Rij rats were randomly divided into four groups (n = 7/group): control, sodium valproate (VPA) 50 mg/kg, VPA 100 mg/kg, and VPA 200 mg/kg. Valproate was administered intraperitoneally once daily for 21 days. The control group received saline (0.5 ml/kg, i.p.). At the end of the treatment period, anxiety-related behavior was assessed using the open field test for 5 minutes under video recording. Horizontal locomotor activity, vertical activity (rearing), and grooming behavior were analyzed.

Results: Compared with the control group, low-dose VPA (50 mg/kg) significantly increased horizontal locomotor activity. Higher doses of VPA did not produce significant changes in locomotion. Grooming behavior increased in the VPA 100 and 200 mg/kg groups, while rearing behavior did not differ between groups.

Conclusion: Chronic VPA at 50 mg/kg increased horizontal activity in the open field, a pattern consistent with an anxiolytic-like profile in this assay. VPA at 100–200 mg/kg increased grooming, indicating a dose-dependent modulation of self-directed behavior; however, because grooming can reflect multiple behavioral states (e.g., stress-coping/displacement, arousal changes, or stereotypy), this finding should not be interpreted as a specific depression-related effect without additional behavioral and ethological analyses.

Keywords: sodium valproate, anxiety-like behavior, depression, absence epilepsy, WAG/Rij rats

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Copyright (c) 2026 The Author(s). This is an open access article distributed under the Creative Commons Attribution License (CC BY), which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited.

How to Cite

1.
Aygün H, Sümbül O. Effects of sodium valproate on anxiety and depression in WAG/Rij rats with absence epilepsy. J Trends Med Invest. 2026;2(1):8-17. https://doi.org/10.64512/JTMI.2026.23

References

  1. Kwon OY, Park SP. Depression and anxiety in people with epilepsy. J Clin Neurol. 2014;10(3):175-88. https://doi.org/10.3988/jcn.2014.10.3.175
  2. Mula M, Kanner AM, Jetté N, Sander JW. Psychiatric comorbidities in people with epilepsy. Neurol Clin Pract. 2021;11(2):e112-e120. https://doi.org/10.1212/CPJ.0000000000000874
  3. Holmes GL. Drug treatment of epilepsy neuropsychiatric comorbidities in children. Paediatr Drugs. 2021;23(1):55-73. https://doi.org/10.1007/s40272-020-00428-w
  4. Coenen AML, Van Luijtelaar ELJM. Genetic animal models for absence epilepsy: a review of the WAG/Rij strain of rats. Behav Genet. 2003;33(6):635-55. https://doi.org/10.1023/a
  5. Sarkisova K, van Luijtelaar G. The WAG/Rij strain: a genetic animal model of absence epilepsy with comorbidity of depression [corrected]. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(4):854-76. https://doi.org/10.1016/j.pnpbp.2010.11.010
  6. Shaw FZ, Chuang SH, Shieh KR, Wang YJ. Depression- and anxiety-like behaviors of a rat model with absence epileptic discharges. Neuroscience. 2009;160(2):382-93. https://doi.org/10.1016/j.neuroscience.2009.02.053
  7. de Los Ángeles Cintado M, De la Casa LG, González G. Anxiolytic and sedative effects of sodium valproate with different experimental paradigms in male and female rats. Neuropsychopharmacol Rep. 2024;44(4):737-748. https://doi.org/10.1002/npr2.12483
  8. Lal H, Shearman GT, Dumn R, Kruse H, Theurer K. Effect of valproic acid on anxiety related behaviors in the rat. Brain Res Bull. 1979;4(5):711. https://doi.org/10.1016/0361-9230(79)90273-9
  9. Schneider Oliveira M, Flávia Furian A, Freire Royes LF, et al. Ascorbate modulates pentylenetetrazol-induced convulsions biphasically. Neuroscience. 2004;128(4):721-8. https://doi.org/10.1016/j.neuroscience.2004.07.012
  10. Ayyildiz M, Coskun S, Yildirim M, Agar E. The effects of ascorbic acid on penicillin-induced epileptiform activity in rats. Epilepsia. 2007;48(7):1388-95. https://doi.org/10.1111/j.1528-1167.2007.01080.x
  11. Aygün H, Aydın D, İnanır S, Ekici F, Ayyıldız M, Ağar E. The effects of agomelatine and melatonin on ECoG activity of absence epilepsy model in WAG/Rij rats. Turk J Biol. 2015;39(6):904-10. https://doi.org/10.3906/biy-1507-32
  12. Coenen AM, Van Luijtelaar EL. The WAG/Rij rat model for absence epilepsy: age and sex factors. Epilepsy Res. 1987;1(5):297-301. https://doi.org/10.1016/0920-1211(87)90005-2
  13. Citraro R, Leo A, De Caro C, et al. Effects of histone deacetylase inhibitors on the development of epilepsy and psychiatric comorbidity in WAG/Rij rats. Mol Neurobiol. 2020;57(1):408-421. https://doi.org/10.1007/s12035-019-01712-8
  14. Jones NC, Salzberg MR, Kumar G, Couper A, Morris MJ, O’Brien TJ. Elevated anxiety and depressive-like behavior in a rat model of genetic generalized epilepsy suggesting common causation. Exp Neurol. 2008;209(1):254-60. https://doi.org/10.1016/j.expneurol.2007.09.026
  15. Yavuz M, Kantarcı BC, Şanlı A, Gavaş Ş, Turgan Aşık ZN, Koyuncuoğlu T. Impact of valproate and levetiracetam exposure on GAERS behavior during pregnancy. Arch Epilepsy. 2023;29(3):69-74. https://doi.org/10.4274/ArchEpilepsy.2023.23098
  16. Singh T, Goel RK. Adjuvant neuronal nitric oxide synthase inhibition for combined treatment of epilepsy and comorbid depression. Pharmacol Rep. 2017;69(1):143-149. https://doi.org/10.1016/j.pharep.2016.10.001
  17. Zalkhani R, Moazedi AA, Ghotbeddin Z, Pourmahdi Borujeni M. The therapeutic effects of low-frequency electrical stimulations adjunct to sodium valproate on seizure and behaviors. Basic Clin Neurosci. 2020;11(1):59-68. https://doi.org/10.32598/bcn.9.10.280
  18. Sarkisova KY, Midzianovskaia IS, Kulikov MA. Depressive-like behavioral alterations and c-fos expression in the dopaminergic brain regions in WAG/Rij rats with genetic absence epilepsy. Behav Brain Res. 2003;144(1-2):211-26. https://doi.org/10.1016/s0166-4328(03)00090-1
  19. Sarkisova KY, Kulikov MA. Behavioral characteristics of WAG/Rij rats susceptible and non-susceptible to audiogenic seizures. Behav Brain Res. 2006;166(1):9-18. https://doi.org/10.1016/j.bbr.2005.07.024
  20. Willner P, Mitchell PJ. The validity of animal models of predisposition to depression. Behav Pharmacol. 2002;13(3):169-88. https://doi.org/10.1097/00008877-200205000-00001
  21. Kalueff AV, Lou YR, Laaksi I, Tuohimaa P. Abnormal behavioral organization of grooming in mice lacking the vitamin D receptor gene. J Neurogenet. 2005;19(1):1-24. https://doi.org/10.1080/01677060590949683
  22. Kalueff AV, Lou YR, Laaksi I, Tuohimaa P. Increased anxiety in mice lacking vitamin D receptor gene. Neuroreport. 2004;15(8):1271-4. https://doi.org/10.1097/01.wnr.0000129370.04248.92
  23. Zou J, Minasyan A, Keisala T, et al. Progressive hearing loss in mice with a mutated vitamin D receptor gene. Audiol Neurootol. 2008;13(4):219-30. https://doi.org/10.1159/000115431
  24. Aygun H. Trazodone increases seizures in a genetic WAG/Rij rat model of absence epilepsy while decreasing them in penicillin-evoked focal seizure model. Epilepsy Behav. 2020;103(Pt A):106847. https://doi.org/10.1016/j.yebeh.2019.106847
  25. Spruijt BM, van Hooff JA, Gispen WH. Ethology and neurobiology of grooming behavior. Physiol Rev. 1992;72(3):825-52. https://doi.org/10.1152/physrev.1992.72.3.825
  26. Kalueff AV, Stewart AM, Song C, Berridge KC, Graybiel AM, Fentress JC. Neurobiology of rodent self-grooming and its value for translational neuroscience. Nat Rev Neurosci. 2016;17(1):45-59. https://doi.org/10.1038/nrn.2015.8
  27. Song C, Berridge KC, Kalueff AV. ‘Stressing’ rodent self-grooming for neuroscience research. Nat Rev Neurosci. 2016;17(9):591. https://doi.org/10.1038/nrn.2016.103
  28. Mu MD, Geng HY, Rong KL, et al. A limbic circuitry involved in emotional stress-induced grooming. Nat Commun. 2020;11(1):2261. https://doi.org/10.1038/s41467-020-16203-x
  29. van Rijn CM, Sun MS, Deckers CLP, et al. Effects of the combination of valproate and ethosuximide on spike wave discharges in WAG/Rij rats. Epilepsy Res. 2004;59(2-3):181-9. https://doi.org/10.1016/j.eplepsyres.2004.04.003
  30. Wahle H, Frey HH. Development of tolerance to the anticonvulsant effect of valproate but not to ethosuximide in a rat model of absence epilepsy. Eur J Pharmacol. 1990;181(1-2):1-8. https://doi.org/10.1016/0014-2999(90)90238-2
  31. De Caro C, Di Cesare Mannelli L, Branca JJV, et al. Pain modulation in WAG/Rij epileptic rats (a genetic model of absence epilepsy): effects of biological and pharmacological histone deacetylase inhibitors. Front Pharmacol. 2020;11:549191. https://doi.org/10.3389/fphar.2020.549191
  32. Rahman M, Awosika AO, Nguyen H. Valproic acid. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2024. Available at: https://www.ncbi.nlm.nih.gov/books/NBK559112/
  33. Töllner K, Wolf S, Löscher W, Gernert M. The anticonvulsant response to valproate in kindled rats is correlated with its effect on neuronal firing in the substantia nigra pars reticulata: a new mechanism of pharmacoresistance. J Neurosci. 2011;31(45):16423-34. https://doi.org/10.1523/JNEUROSCI.2506-11.2011
  34. Badawy AA, Elghaba R, Soliman M, et al. Chronic valproic acid administration increases plasma, liver, and brain ammonia concentration and suppresses glutamine synthetase activity. Brain Sci. 2020;10(10):759. https://doi.org/10.3390/brainsci10100759