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Chronic oral carbamazepine treatment elicits mood-stabilising effects in mice

  • Nirit Z. Kara (a1) (a2), Orit Karpel (a2), Lilach Toker (a2), Galila Agam (a2) (a3), Robert H. Belmaker (a3) and Haim Einat (a1) (a2) (a4)...



The underlying biology of bipolar disorder and the mechanisms by which effective medications induce their therapeutic effects are not clear. Appropriate use of animal models are essential to further understand biological mechanisms of disease and treatment, and further understanding the therapeutic mechanism of mood stabilisers requires that clinically relevant administration will be effective in animal models. The clinical regimens for mood-stabilising drugs include chronic oral administration; however, much of the work with animal models includes acute administration via injection. An effective chronic and oral administration of the prototypic mood stabiliser lithium was already established and the present study was designed to do the same for the mood stabiliser carbamazepine.


Mice were treated for 3 weeks with carbamazepine in food. ICR mice were treated with 0.25%, 0.5% and 0.75%, and C57bl/6 mice with 0.5% and 0.75%, carbamazepine in food (w/w, namely, 2.5, 5.0 or 7.5 g/kg food). Mice were then tested for spontaneous activity, forced swim test (FST), tail suspension test (TST) and amphetamine-induced hyperactivity.


Oral carbamazepine administration resulted in dose-dependent blood levels reaching 3.65 μg/ml at the highest dose. In ICR mice, carbamazepine at the 0.5% dose had no effect on spontaneous activity, but significantly reduced immobility in the TST by 27% and amphetamine-induced hyperactivity by 28%. In C57bl/6 mice, carbamazepine at the 0.75% dose reduced immobility time in the FST by 26%.


These results demonstrate a behaviourally effective oral and chronic regimen for carbamazepine with mood stabilising-like activity in a standard model for mania-like behaviour and two standard models for depression-like behaviour.


Corresponding author

Haim Einat, School of Behavioral Sciences, Tel Aviv-Yaffo Academic College, 2 Rabenu Yeruham St., Tel-Aviv, Israel. Tel: (972)3-680-2536; Fax: (972)3-680-2526; E-mail:


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1.Belmaker, RH. Bipolar disorder. N Engl J Med 2004;351:476486.
2.Gould, TD, Quiroz, JA, Singh, J, Zarate, CA, Manji, HK. Emerging experimental therapeutics for bipolar disorder: insights from the molecular and cellular actions of current mood stabilizers. Mol Psychiatry 2004;9:734755.
3.Einat, H. Modelling facets of mania – new directions related to the notion of endophenotypes. J Psychopharmacol 2006;20:714722.
4.Einat, H. Different behaviors and different strains: potential new ways to model bipolar disorder. Neurosci Biobehav Rev 2007;31:850857.
5.Cox, C, Harrison-Read, PE, Steinberg, H, Tomkiewicz, M. Lithium attenuates drug-induced hyperactivity in rats. Nature 1971;232:336338.
6.Cryns, K, Shamir, A, Shapiro, Jet al. Lack of lithium-like behavioral and molecular effects in IMPA2 knockout mice. Neuropsychopharmacology 2007;32:881891.
7.Einat, H, Yuan, P, Szabo, ST, Dogra, S, Manji, HK. Protein kinase C inhibition by tamoxifen antagonizes manic-like behavior in rats: implications for the development of novel therapeutics for bipolar disorder. Neuropsychobiology 2007;55:123131.
8.Gould, TD, Einat, H. Animal models of bipolar disorder and mood stabilizer efficacy: a critical need for improvement. Neurosci Biobehav Rev 2007;31:825831.
9.O'Brien, WT, Harper, AD, Jove, Fet al. Glycogen synthase kinase-3beta haploinsufficiency mimics the behavioral and molecular effects of lithium. J Neurosci 2004;24:67916798.
10.Bersudsky, Y, Shaldubina, A, Belmaker, RH. Lithium's effect in forced-swim test is blood level dependent but not dependent on weight loss. Behav Pharmacol 2007;18:7780.
11.Kovacsics, CE, Gould, TD. Shock-induced aggression in mice is modified by lithium. Pharmacol Biochem Behav 2009;94:380386.
12.Arban, R, Maraia, G, Brackenborough, Ket al. Evaluation of the effects of lamotrigine, valproate and carbamazepine in a rodent model of mania. Behav Brain Res 2005;158:123132.
13.Kalinichev, M, Dawson, LA. Evidence for antimanic efficacy of glycogen synthase kinase-3 (GSK-3) inhibitors in a strain specific model of acute mania. Int J Neuropsychopharmacol 2011;6:117.
14.Elphick, M. Effects of carbamazepine on dopamine function in rodents. Psychopharmacology (Berlin) 1989;99:532536.
15.Barros, HM, Leite, JR. The effects of carbamazepine on two animal models of depression. Psychopharmacology (Berlin) 1987;92:340342.
16.Kitamura, Y, Akiyama, K, Kitagawa, Ket al. Chronic coadministration of carbamazepine together with imipramine produces antidepressant-like effects in an ACTH-induced animal model of treatment-resistant depression: involvement of 5-HT(2A) receptors? Pharmacol Biochem Behav 2008;89:235240.
17.Shaldubina, A, Einat, H, Szechtman, H, Shimon, H, Belmaker, RH. Preliminary evaluation of oral anticonvulsant treatment in the quinpirole model of bipolar disorder. J Neural Transm 2002;109:433440.
18.Chen, J, Cai, F, Cao, J, Zhang, X, Li, S. Long-term antiepileptic drug administration during early life inhibits hippocampal neurogenesis in the developing brain. J Neurosci Res 2009;87:28982907.
19.Szymczyk, G, Zebrowska-Lupina, I. Influence of antiepileptics on efficacy of antidepressant drugs in forced swimming test. Pol J Pharmacol 2000;52:337344.
20.Post, RM, Ketter, TA, Uhde, T, Ballenger, JC. Thirty years of clinical experience with carbamazepine in the treatment of bipolar illness: principles and practice. CNS Drugs 2007;21:4771.
21.Fountoulakis, KN, Grunze, H, Panagiotidis, P, Kaprinis, G. Treatment of bipolar depression: an update. J Affect Disord 2008;109:2134.
22.Ali, A, Dua, Y, Constance, JE, Franklin, MR, Dudek, FE. A once-per-day, drug-in-food protocol for prolonged administration of antiepileptic drugs in animal models. Epilepsia 2012;53:199206.


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Chronic oral carbamazepine treatment elicits mood-stabilising effects in mice

  • Nirit Z. Kara (a1) (a2), Orit Karpel (a2), Lilach Toker (a2), Galila Agam (a2) (a3), Robert H. Belmaker (a3) and Haim Einat (a1) (a2) (a4)...


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