Extracellular GABA in the Ventrolateral Thalamus of Rats Exhibiting Spontaneous Absence Epilepsy: A Microdialysis Study

Abstract

There is compelling evidence that excessive GABA‐mediated inhibition may underlie the abnormal electrical activity, initiated in the thalamus, associated with epileptic absence seizures. In particular, the GABAB receptor subtype seems to play a critical role, because its antagonists are potent inhibitors of absence seizures, whereas its agonists exacerbate seizure activity. Using a validated rat model of absence epilepsy, we have previously found no evidence of abnormal GABAB receptor density or affinity in thalamic tissue. In the present study, we have used in vivo microdialysis to monitor changes in levels of extracellular GABA and other amino acids in this brain region. We have shown that basal extracellular levels of GABA and, to a lesser extent, taurine are increased when compared with values in nonepileptic controls. However, modifying GABAergic transmission with the GABAB agonist (−)‐baclofen (2 mg/kg i.p.), the GABAB antagonist CGP‐35348 (200 mg/kg i.p.), or the GABA uptake inhibitor tiagabine (100 µM) did not produce any further alteration in extracellular GABA levels, despite the ability of these compounds to increase (baclofen and tiagabine) or decrease (CGP‐35348) seizure activity. These findings suggest that the increased basal GABA levels observed in this animal model are not simply a consequence of seizure activity but may contribute to the initiation of absence seizures.

The Effects of Ethosuximide on Amino Acids in Genetic Absence Epilepsy Rat Model

“…Therefore, the role of the component parts of this circuitry is still a matter of debate. In the present study, we once more demonstrated the increased basal GABA concentrations in the M1 area and partly the VLT of non-treated GAERS compared to those of Wistar rats as in non-epileptic control rats in accordance to the previous findings (9,10). In view of these informations, we can conclude that there is increased basal GABA level primarily in the M1 area and partly in the VLT of non-treated GAERS, and the pharmacological effects of ETX on the GABA level denoted the importance of corticothalamic circuitry in the genetic model of absence epilepsy.…”

“…Excess γ-aminobutyric acid (GABA) mediated activity has been suggested in the pathogenesis of absence seizures since longstanding hyperpolarization is required to activate low-threshold Ca 2+ currents (8). The GABA levels were detected to be higher in the ventrolateral thalamus (VLT) of GAERS compared to nonepileptic controls in a previous microdialysis study (9). In a preliminary report, we also demonstrated that GABA levels were increased in the primary motor cortex (M1) area (10).…”

Comparison of numbers of interneurons in three thalamic nuclei of normal and epileptic rats

“…There is considerable evidence that thalamic nuclei, primarily the VB nucleus, are involved in the propagation and regulation of seizures [31,52] . Previous findings using a microdialysis method also showed increased levels of extracellular GABA in the VB thalamus of GAERS compared to nonepileptic control Wistar rats [53] . Danober et al [34] reported that the VB nucleus is critical in controlling the oscillatory thalamocortical activity that underlies generalized epileptic seizures such as absence seizures.…”

Seizures in a pediatric patient with a tiagabine overdose

“…A study in rats suggests that the epileptic effect may be mediated through other mechanisms in different parts of the CNS such as the thalamus [17]. Other potential mechanisms include TGB stimulation of dopamine, serotonin, or glycine receptors in different areas in the brain.…”