cgp-56999a and Epilepsy--Absence

Absence seizures have a clearly defined thalamocortical origin. However, there is evidence from a genetic rat model of absence epilepsy, GAERS, that the underlying cellular and molecular abnormalities may also manifest themselves in other brain regions. As enhanced learning has previously been associated with this rat model, we have studied extracellular amino acid levels and EEG spectra in the hippocampus of these rats, this being a brain region associated with memory and learning. We report significantly higher levels of basal extracellular glutamate within the hippocampus of GAERS, together with transient increases in citrulline and glycine following aggravation of the absence seizures with the GABA(B) agonist, (-)baclofen. Furthermore, there is a reduction in the relative power of the EEG theta frequencies in GAERS, and a slowing of the EEG following administration of (-)baclofen which is not evident in control animals. Administration of a GABA(B) antagonist, CGP 56999, at a dose which blocks absence seizures in GAERS, caused a shift to faster frequencies of the EEG in both GAERS and control rats. It is speculated that the mechanisms underlying absence seizures in GAERS may manifest themselves in other functions modulated by thalamocortical oscillations such as cognitive processing.

Topics: Amino Acids; Animals; Baclofen; Electroencephalography; Epilepsy, Absence; Extracellular Space; Female; GABA Agonists; GABA Antagonists; Hippocampus; Microdialysis; Phosphinic Acids; Rats; Rats, Wistar

In Wistar rats with spontaneous non-convulsive absence epilepsy, absence seizures were dose dependently suppressed by intraperitoneal administration of the GABAB receptor antagonists CGP 36742, 50-400 mg/kg, and CGP 56999, 0.25-0.75 mg/kg, and by bilateral microinjections of the same compounds into the lateral nuclei of the thalamus. In rats susceptible to audiogenic seizures, intraperitoneal administration of both GABAB receptor antagonists, at doses which suppressed absence seizures, facilitated the elicitation of sound-induced tonic seizures. In non-epileptic control rats, intraperitoneal injections of higher doses of CGP 36742 (800-2400 mg/kg) and CGP 56999 (3-6 mg/kg) induced delayed clonic convulsions, which were suppressed by pretreatment with baclofen. c-Fos protein was expressed after GABAB receptor antagonist-induced seizures in the cortex, hippocampus, amygdala, perirhinal and piriform cortex. Intra-cortical and hippocampal microinfusion of both GABAB receptor antagonists produced focal seizures. In conclusion, GABAB receptor antagonists suppress non-convulsive absence seizures by blocking thalamic GABAB receptors, while they induce convulsions in cortical and limbic structures.

Topics: Animals; Brain; Epilepsy, Absence; GABA Antagonists; GABA-B Receptor Antagonists; Male; Organophosphorus Compounds; Phosphinic Acids; Proto-Oncogene Proteins c-fos; Rats; Seizures