Abstracts

Aggravation of seizures by anti-epileptic drugs is an important clinical problem. A well-documented example of this is the aggravation of absence seizures by carbamazepine (CBZ), but the mechanisms are very poorly understood. Generalized absence epilepsy rats of Strasbourg (GAERS) are a well-validated model of genetic absence epilepsy. Critical to the neurophysiology of absence seizures are the reticular nucleus (Rt) and the ventrobasal nucleus (VB) of the thalamus. The aim of this study was to investigate the effects of microinjection of CBZ into the Rt and the VB on seizure expression. Female ovarectomised GAERS were implanted with either intracerebroventricular (icv) cannulae or bilateral microcatheters into the Rt or VB, and extradural EEG electrodes. Rats were studied following injection of CBZ (icv: 10ug in 4uL or Rt/VB: 0.75ug in 0.2uL) or vehicle (in random order). The treatment effect was quantified over a 90-minute EEG recording. Seizure aggravation was seen in all rats (n=7) given CBZ icv (mean increase in seizure time = 49 [plusmn] 26% p[lt]0.05). Similar seizure aggravation was seen after microinjection of CBZ into the VB (56 [plusmn] 17%, [italic]P [/italic]= 0.01, n=7) No effects on seizures were observed following CBZ administration into the Rt (-8 [plusmn] 12%, n=7). When a further groups of rats underwent injections into the VB of CBZ, CBZ with the GABA-A antagonist bicuculline (CBZ-BIC), bicuculline alone, or vehicle there was significantly less seizure aggravation following CBZ-BIC (21 [plusmn] 12%, n=10) than following CBZ alone (151 [plusmn] 23%, n=5) (p=0.02). This data indicates that the VB is the neuroanatomical site at which CBZ acts to aggravate absence seizures, and that activation of GABA-A receptors are important in the mechanism of this effect.