title: The mechanism of carbamazepine aggravation of absence seizures.
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 GABA(A) 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 microg in 4 microl) 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 microg in 0.2 microl) into the VB (53%) but not following injection into the Rt (-9%). However, seizure aggravation was blocked when the GABA(A) receptor antagonist, bicuculline (BIC, 0.04 microg in 0.2 microl), 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 GABA(A) receptors demonstrated that CBZ produced a dose-dependent potentiation of the GABA current at a physiological relevant concentration range (1-100 microM). These data demonstrate that CBZ acts at the VB thalamus to aggravate absence seizures in GAERS and that activation of GABA(A) receptors is critical to this effect.
authors.affiliation: Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Royal Parade, Parkville 3050, Victoria, Australia.
authors.forename: Lige
authors.initials: L
authors.lastname: Liu
authors.forename: Thomas
authors.initials: T
authors.lastname: Zheng
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Morris
authors.forename: Charlott
authors.initials: C
authors.lastname: Wallengren
authors.forename: Alison L
authors.initials: AL
authors.lastname: Clarke
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reid
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects*; D001921:Brain / Q000187:drug effects; D002220:Carbamazepine / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004832:Epilepsy, Absence / Q000209:etiology*; D058787:GABA-A Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D013788:Thalamus / Q000187:drug effects; D014981:Xenopus
chemical_list: D000927:Anticonvulsants; D058787:GABA-A Receptor Antagonists; D002220:Carbamazepine