Abstract for presentation at 21st Annual Scientific Meeting of the Epilepsy Society of Australia

Modulation of GABAA receptors by carbamazepine

  • Mr Thomas Zheng, Department of Medicine, The University of Melbourne, Australia
  • Dr Alison Clark, The Howard Florey Institute of Physiology and Medicine, Australia
  • Prof Margaret Morris, Department of Physiology and Pharmacology, University of New South Wales, Australia
  • Dr Christopher Reid, The Howard Florey Institute of Physiology and Medicine, Australia
  • Dr Steven Petrou, The Howard Florey Institute of Physiology and Medicine, Australia
  • Associate Professor Terence O'Brien, Department of Medicine, Neurology, Surgery, The University of Melbourne, Australia

    • Introduction: Carbamazpine (CBZ) is a first-line anti-epileptic drug, but is known to aggravate certain types of generalized seizures in humans and animal models. In vivo studies in the Genetic Absence Epileptic Rats from Strasbourg (GAERS) have indicated that enhancement of GABAA receptor activity may play a critical role the mechanism underlying this aggravation. However, it is uncertain whether this is a direct or indirect effect of CBZ. Two in vitro techniques were used to investigate the direct effect of CBZ on GABAA receptor function.
    Methods: 1) Using brain synaptic vesicular preparations from cortex and thalamus of GAERS, GABAA receptor-mediated 36Chloride uptake was measured in the presence of several combinations of CBZ and GABA, with and without the addition of the GABAA receptor antagonist – bicuculline (BIC). 2) Utilizing Xenopus oocytes expressing recombinant GABAA receptors (subunit combination α1β2γ2), the effect of CBZ (0.1-100 μM) in the presence of GABA (EC20; 6x10-6M) on receptor function was investigated.
    Results: 1) 36Cl- uptake measurements in synaptic vesicles demonstrated a dose-dependent increase in Cl- uptake induced by CBZ (1 - 1000 μM). This was completely blocked by BIC. The magnitude of the enhanced receptor activity was greater in the preparations from the thalamus (51%) than the cortex (25%). In Xenopus oocytes expressing GABAA receptors, CBZ potentiated the GABA-induced current in a dose-dependent manner at physiological concentrations (1 - 100 μM).
    Conclusion: These data suggest that CBZ does interact directly with GABAA receptors at physiologically relevant concentrations. The data from 36Cl- uptake study demonstrates that this occurs in brain regions integral to development of absence seizures in animals with genetic generalized epilepsy. This supports the in vivo data indicating that enhancement of GABAA receptor-mediated activity in the thalamus may be the mechanism underlying the aggravation of absence seizures by CBZ.

    Conference Organiser - ICMS Pty Ltd