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Research ArticleNEUROPHARMACOLOGY

The Mechanism of Carbamazepine Aggravation of Absence Seizures

Lige Liu, Thomas Zheng, Margaret J. Morris, Charlott Wallengren, Alison L. Clarke, Christopher A. Reid, Steven Petrou and Terence J. O'Brien
Journal of Pharmacology and Experimental Therapeutics November 2006, 319 (2) 790-798; DOI: https://doi.org/10.1124/jpet.106.104968
Lige Liu
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Thomas Zheng
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Margaret J. Morris
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Charlott Wallengren
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Alison L. Clarke
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Christopher A. Reid
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Steven Petrou
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Terence J. O'Brien
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Abstract

Carbamazepine (CBZ) aggravates many generalized seizures types, particularly absence seizures, but the mechanisms underlying this are poorly understood. GABA signaling within the reticular nucleus (Rt) and the ventrobasal complex (VB) of the thalamus is critical to the neurophysiology of absence seizures. The hypothesis that CBZ aggravates absence seizures by acting at the VB thalamus via a GABAA receptor-mediated mechanism was investigated in a genetic rat model, generalized absence epilepsy rats from Strasbourg (GAERS). Seizure activity was quantified by a 90-min electroencephalogram recording postdrug injection. Intracerebroventricular injections of CBZ (15 μg in 4 μl) resulted in seizure aggravation versus vehicle treatment, with a mean increase in seizure time of 40%. This indicates that CBZ acts directly, rather than via a metabolite, on the brain to aggravate seizures. Seizure aggravation also occurred following bilateral microinjection of CBZ (0.75 μg in 0.2 μl) into the VB (53%) but not following injection into the Rt (–9%). However, seizure aggravation was blocked when the GABAA receptor antagonist, bicuculline (BIC, 0.04 μg in 0.2 μl), was coinjected with CBZ into the VB. Injection of BIC alone (versus vehicle) into the VB also blocked seizure aggravation following systemic administration of CBZ (15 mg/kg i.p.). In vitro studies in Xenopus oocytes expressing recombinant GABAA receptors demonstrated that CBZ produced a dose-dependent potentiation of the GABA current at a physiological relevant concentration range (1–100 μM). These data demonstrate that CBZ acts at the VB thalamus to aggravate absence seizures in GAERS and that activation of GABAA receptors is critical to this effect.

Footnotes

  • This work was supported by The Sylvia and Charles Viertel Charitable Foundation (Investigator Grant to T.J.O.), by a Project Grant from The Friends of The Royal Melbourne Hospital Neuroscience, and by a Project Grant from the National Health and Medical Research Council of Australia (Project Grant 400106 to M.M., T.J.O., and C.R.). The EEG recording equipment was loaned by Compumedics, Melbourne, Australia.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.106.104968.

  • ABBREVIATIONS: AED, antiepileptic drug; CBZ, carbamazepine; GAERS, generalized absence epilepsy rats from Strasbourg; EEG, electroencephalogram; SWD, spike and wave discharge; Rt, reticular nucleus of the thalamus; VB, ventrobasal thalamus; CSF, cerebrospinal fluid; BIC, bicuculline; ANOVA, analysis of variance; i.c.v., intracerebroventricular; i.p., intraperitoneal.

  • ↵1 These authors contributed equally to this work.

    • Received March 21, 2006.
    • Accepted August 3, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleNEUROPHARMACOLOGY

The Mechanism of Carbamazepine Aggravation of Absence Seizures

Lige Liu, Thomas Zheng, Margaret J. Morris, Charlott Wallengren, Alison L. Clarke, Christopher A. Reid, Steven Petrou and Terence J. O'Brien
Journal of Pharmacology and Experimental Therapeutics November 1, 2006, 319 (2) 790-798; DOI: https://doi.org/10.1124/jpet.106.104968

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Research ArticleNEUROPHARMACOLOGY

The Mechanism of Carbamazepine Aggravation of Absence Seizures

Lige Liu, Thomas Zheng, Margaret J. Morris, Charlott Wallengren, Alison L. Clarke, Christopher A. Reid, Steven Petrou and Terence J. O'Brien
Journal of Pharmacology and Experimental Therapeutics November 1, 2006, 319 (2) 790-798; DOI: https://doi.org/10.1124/jpet.106.104968
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