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.