International Journal of Clinical and Experimental Neurology
ISSN (Print): 2379-7789 ISSN (Online): 2379-7797 Website: Editor-in-chief: Zhiyou Cai, MD
Open Access
Journal Browser
International Journal of Clinical and Experimental Neurology. 2015, 3(2), 32-44
DOI: 10.12691/ijcen-3-2-2
Open AccessArticle

Behavioral and Neurochemical Characteristics of Two Months Old WAG/Rij Rats with Genetic Absence Epilepsy

E. A. Fedosova1, K. Yu. Sarkisova1, V. S. Kudrin2, V. B. Narkevich2 and A. S. Bazyan1,

1Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow, Russia

2State Zakusov Institute of Pharmacology, Russian Academy of Medical Sciences, Moscow, Russia

Pub. Date: August 20, 2015

Cite this paper:
E. A. Fedosova, K. Yu. Sarkisova, V. S. Kudrin, V. B. Narkevich and A. S. Bazyan. Behavioral and Neurochemical Characteristics of Two Months Old WAG/Rij Rats with Genetic Absence Epilepsy. International Journal of Clinical and Experimental Neurology. 2015; 3(2):32-44. doi: 10.12691/ijcen-3-2-2


WAG/Rij rats are genetic animal model of absence epilepsy with comorbidity of depression. The first spike-wave discharges (SWDs) in WAG/Rij rats begin to appear at the age of 2-3 months and are fully manifested by 5-6 months. Occurrence of SWDs in the EEG is the main index of absence epilepsy. Previously it has been shown that the extensive absence epilepsy in 5-6 months old WAG/Rij rats is accompanied by decrease of dopamine and its metabolites concentrations in the meso-cortico-limbic and nigro-striatal dopaminergic brain systems, resulting in the expression of depression-like behavioral symptoms, and impairments of the learning and memory processes. In 36 days old WAG/Rij rats, SWDs are not manifested, deficiency of the mesolimbic dopamine is not revealed, and symptoms of depression-like behavior are not expressed. In this study, behavior in the open field, light-dark choice, forced swimming tests, monoamines and their metabolites concentrations in 5 brain structures (prefrontal cortex, nucleus accumbens, hypothalamus, striatum, hippocampus) were investigated in two months old WAG/Rij rats in comparison with age-matched Wistar rats. Reduced concentration of the dopamine and its metabolites, and increased concentration of the serotonin was found in WAG/Rij rats compared with Wistar rats only in the prefrontal cortex, indicating that the prefrontal cortex is the brain structure where neurochemical abnormalities appear first. No substantial changes in the monoamine and their metabolites concentrations have been revealed in other brain structures. Two months old WAG/Rij rats didn’t exhibit depression-like behavior in the forced swimming test, and learning/memory deficits in the passive avoidance test, but they showed behavioral changes, indicating increase anxiety/stress-reactivity, and alterations in learning/memory in the active avoidance test. Results suggest that two month-old WAG/Rij rats are at the stage of so called “pre-pathology” (increased anxiety and stress reactivity) preceding the development of depression-like behavior and substantial cognitive impairments which are co-morbid to fully expressed absence epilepsy in 5-6 months old rats of this strain.

2 months old WAG/Rij rats monoamines dopamine anxiety depression-like behavior learning and memory

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit


[1]  Barson JR, Morganstern I, Leibowitz SF (2011). Similarities in hypothalamic and mesocorticolimbic circuits regulating the overconsumption of food and alcohol. Physiol Behav; 104 (1): 128-137.
[2]  Bazyan AS (1999). Neuromodulators and integrative mechanisms of emotional and motivation states. Neurochemical Journal; 16 (2): 88-103.
[3]  Bazyan AS, Orlova NV, Getsova VM (2000). Modulation of the activity of monoaminergic brain systems and emotional condition by dalargin in rats during development of emotional resonance response. Zh Vyssh Nerv Deiat Im I P Pavlova; 50(3): 500-508.
[4]  Bazyan AS (2001). Divergent and convergent mechanisms of the integrative activity of the mammalian brain. Zh Vyssh Nerv Deiat Im I P Pavlova; 51(4): 514-528.
[5]  Bazyan AS, Segal OL (2009). Synaptic and paracrine nonsynaptic systems of the mammalian brain. Neurochemical Journal; 3(2): 77-86.
[6]  Bazyan AS, Grigir'ian GA, Ioffe ME, 2011. Regulation of motor behaviour. Usp Fiziol Nauk; 42(3): 65-80.
[7]  Bazyan AS, and van Luijtelaar G (2013). Review article. Neurochemical and behavioral features in genetic absence epilepsy and in acutely induced absence seizures. ISRN Neurology. Art. ID 875834.
[8]  Bechara A, Damasio AR (2005). The somatic marker hypothesis: a neural theory of economic decision. Games and Econom. Behav; 52 (2): 336-372.
[9]  Braw Y, Malkesman O, Dagan M, Bercovich A, Lavi-Avnon Y, Schroeder M, Overstreet DH, Weller A (2006). Anxiety-like behaviors in pre-pubertal rats of the Flinders Sensitive Line (FSL) and Wistar-Kyoto (WKY) animal models of depression. Behav. Brain Res; 167 (2): 261-269.
[10]  Calatayud F, Belzung C, Aubert A (2004). Ethological validation and the assessment of anxiety-like behaviors: methodological comparison of classical analysis and structural approaches. Behav Processes; 67(2): 195-206.
[11]  Carlezon WAJr, Thomas MJ (2009). Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis. Neuropharmacol; 56 (1): 122-132.
[12]  Costall B, Jones BJ, Kelly ME, Neylor RJ, Tomkins DM, (1989). Exploration of mice in a black and white test box: validation as a model of anxiety. Pharmacol Biochem Behav; 32(3): 777-785.
[13]  Cryan JF, Lucki I (2000). Antidepressant-like behavioral effects mediated by 5-hydroxytryptamine (2C) receptors. Pharmacol. Exp. Ther; 295(3): 1120-1126.
[14]  Deneve S, (2012). Making decisions with unknown sensory reliability. Front Neurosci. 6:75.
[15]  Espejo EF (1997). Selective dopamine depletion within the medial prefrontal cortex induces anxiogenic-like effects in rats placed on the elevated plus maze. Brain Res; 762(1-2): 281-284.
[16]  Garcia-Cairasco N, Oliveira JAC, Wakamatsu H, Bueno ST, Guimaraes FS (1998). Reduced exploratory activity of audiogenic seizure susceptible Wistar rats. Physiol Behav; 64(5): 671-674.
[17]  Gonzalez C, Kramar C, Garagoli F, Rossato JI, Weisstaub N, Cammarota M, Medina JH (2013). Medial prefrontal cortex is a crucial node of a rapid learning system that retrieves recent and remote memories. Neurobiol. Learn. Mem; 103: 19-25.
[18]  Griebel G., Rodgers R., Perrault C.H, Sanger D.J., 1997. Risk assessment behavior: evaluation of utility in the study of 5-HT-related drugs in the rat elevated plus-maze test. Pharmacol Biochem Behav. 57(4): 817-827.
[19]  Gruber A.J., McDonald R.J. 2012. Context, emotion, and the strategic pursuit of goals: interactions among multiple brain systems controlling motivated behavior. Front Behav Neurosci; 6: 50.
[20]  Hascoët M., Bourin M., Nic Dhonnchadha B.Á., 2001. The mouse ligth-dark paradigm: A review. Prog. Neuropsychopharmacol. Bio. Psychiatry; 25(1): 141-166.
[21]  Ho S.S., Gonzalez R.D., Abelson J.L., Liberzon I., 2012. Neurocircuits underlying cognition-emotion interaction in a social decision making context. Neuroimage; 63(2): 843-537.
[22]  Jüngling K, Seidenbecher T, Sosulina L, Lesting J, Sangha S, Clark SD, Okamura N, Duangdao DM, Xu Y-L, Reinscheid RK, Pape H-C (2008). Neuropeptide S-mediated control of fear expression and extinction: Role of intercalated GABAergic neurons in the amygdala. Neuron; 59(2): 298–310.
[23]  King D, Zigmond MJ, Finlay JM (1997). Effects of dopamine depletion in the medial prefrontal cortex on the stress-induced increases in extracellular dopamine in the nucleus accumbens and shell. Neurology; 77(1): 141-153.
[24]  Li B, Piriz J, Mirrione M, Chung C, Proulx CD, Schulz D, Henn F, Malinow R (2011). Synaptic potentiation onto habenula neurons in learned helplessness model of depression. Nature; 470(7335): 535-539.
[25]  Lucki I (1997). The forced swimming test as a model for core and component behavioral effects of antidepressant drugs. Behav. Pharmacol; 8(6-7): 523-532.
[26]  Matveeva MI, Shtemberg AS, Timoshenko GN, Krasavin EA, Narkevich VB, Klodt PM, Kudrin VS, Bazyan AS (2013). The effects of irradiation by 12C carbon ions on monoamine exchange in several rat brain structures. Neurochemical Journal; 7(4): 303–307.
[27]  Mink JW (2003). The basal ganglia. Fundamental neuroscience. 2nd/Ed. Scuire LR, Bloom FT, McConnell SC, Roberts JL, Spitzer NC, Zigmond MJ. Elsevier Sci.: Acad. Press; 815-839.
[28]  Morrow A.L., Porcu P., Boyd K.N., Grant K.A., 2006. Hypothalamic-pituitary-adrenal axis modulation of GABAergic neuroactive steroids influences ethanol sensitivity and drinking behavior. Dialogues Clin. Neurosci; 8(4): 463-477.
[29]  Naitoh H, Nomura S, Kunimi Y, Yamaoka K (1992). "Swimming-induced head twitching" in rats in the forced swimming test induced by overcrowding stress: a new marker in the animal model of depression? Keio J Med; 41(4): 221-224.
[30]  Nozek K, Dennis K, Andrus BM, Ahmadiyeh N, Baum AE, Woods LC, Redei EE (2008). Context and stress-dependent behavioral response to stress. Behav. Brain Functions; 4:23.
[31]  Porsolt RD, Lenegre A (1992). Behavioral models of depression. In Elliot J.M., Heal D.J., Marsden C.A. (Eds) Experimental approaches to anxiety and depression. Willey, New York; 73-85.
[32]  Prut L, Belzung C (2003). The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol; 463(1-3): 3-33.
[33]  Przybycien-Szymanska MM, Gillespie RA, Pak TR (2012). 17β-Estradiol is required for the sexually dimorphic effects of repeated binge-pattern alcohol exposure on the HPA axis during adolescence. PLoS One; 7 (2):e32263.
[34]  Sarkisova KYu, Kolomeitseva IA, Kulikov MA (1996). Effects of substance P on behavioral measures in the open field and forced swimming tests in rats with different type of behavior. Bull Exp Biol Med; 121: 244-247.
[35]  Sarkisova KYu, Kulikov MA, (1994). Individual differences in reaction to acute stress associated with type of behavior. Prediction of the resistance to stress. Bull Exp Biol Med; 117: 89-92.
[36]  Sarkisova KYu, Kulikov MA (2001). Prophylactic action of the antioxidant agent AEKOL on behavioral (psycho-emotional) disturbances induced by chronic stress in rats. Neurosci Behav Physiol; 31(5): 503-508.
[37]  Sarkisova KYu, Midzyanovskaya IS, Kulikov MA (2003). Depressive-like behavioral alterations and c-fos expression in the dopaminergic brain regions in WAG/Rij rats with genetic absence epilepsy. Behav Brain Res; 144(1-2): 211-226.
[38]  Sarkisova KYu, Kulikov MA (2006). Behavioral characteristics of WAG/Rij rats susceptible and non-susceptible to audiogenisc seizures. Behav Brain Res; 166(1): 9-18.
[39]  Sarkisova KYu, Kulikov MA, Midzyanovskaya IS, Folomkina AA (2008). Dopamine-dependent nature of depression-like behavior in WAG/Rij rats with genetic absence epilepsy. Neurosci Behav Physiol; 38(2): 119-128.
[40]  Sarkisova KYu, Kulikov MA, Folomkina AA (2011). Does antiabsence drug ethosuximide exert antidepressant effect? Zh Vyssh Nerv Deiat Im I P Pavlova: 61(2):227-235.
[41]  Sarkisova K, van Luijtelaar G (2011). Review article. The WAG/Rij strain: a genetic animal model of absence epilepsy with comorbidity of depression. Prog. Neuro-Psychopharmacol. Biol. Psychiatry; 5(4): 854-876.
[42]  Sarkisova KYu, Kulikov MA, Kudrin VS, Narkevich VB, Midzyanovskaya I.S., Birioukova LM, Folomkina AA, Bazyan A.S (2013a). Neurochemical mechanisms of depression-like behavior in WAG/Rij rats. Zh. Vyssh. Nerv. Deiat. Im I P Pavlova; 63(3): 303-315.
[43]  Sarkisova KYu, Kulikov MA, Midzyanovskaya IS, Birioukova LM, Kudrin VS (2013b). Neurochemical mechanisms of depression in absence epilepsy. Abstracts IX International interdisciplinary congress "Neuroscience for medicine and psychology", Sudak, Crimea, Ukraine, June 3-13, P. 279-280.
[44]  Shumake J, Ilango A, Scheich H, Wetzel W, Ohl FW (2010). Differential neuromodulation of acquisition and retrieval of avoidance learning by the lateral habenula and ventral tegmental area. J Neurosci; 30(17): 5876-5883.
[45]  Tanji J, Hoshi E (2008). Role of the lateral prefrontal cortex in executive behavioral control. Physiol Rev; 88(1): 37-57.
[46]  Takao K., Miyakawa T., 2006. Light/dark transition test for mice. J Vis Exp. Nov; 13(1): 104.
[47]  Zaitsev AV, Lewis DA (2013). Functional properties and short-term dynamics of unidirectional and reciprocal synaptic connections between layer 2/3 pyramidal cells and fast-spiking interneurons in juvenile rat prefrontal cortex. Eur J Neurosci; 38(7): 2988-2998.
[48]  Zhou WL, Antic SD (2012). Rapid dopaminergic and GABAergic modulation of calcium and voltage transients in dendrites of prefrontal cortex pyramidal neurons. J Physiol; 590(16): 3891-3911.