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PET Studies of Generalized Epilepsy Induced by Convulsant Drugs Acting at the GABA-Benzodiazepine Receptor Complex

  • M. Mazière
  • E. Brouillet
  • M. Kunimoto
  • M. Khalili-Varasteh
  • Ph. Hantraye
  • R. H. Dodd
  • D. Fournier
  • B. Guibert
  • C. Chavoix

Abstract

The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has been implicated in the control of seizures activity, as shown by changes in GABA levels observed after the administration of convulsant or anticonvulsant drugs (Meldrum, 1981). The GABA mediates its anticonvulsant action by binding to the supramolecular receptor complex (Schoch et al., 1984), the GABA-benzo-diazepine receptor (GABA-BZ-R), and opening an integral chloride channel (Stephenson and Barnard, 1986). Postsynaptic responses to GABA are mediated through alterations in chloride conductance that, mostly, lead to hy-perpolarization of the cell and result in a decrease in neuronal activity. GABAergic transmission can be modulated by drugs affecting GABA synaptic activity by acting at different specific binding sites of the GABA-BZ-R. During the last decade, it has been shown that this supramolecular complex associated with postsynaptic responses is a site of action for a number of structurally unrelated compounds able to modulate postsynaptic responses to GABA. Depending on their modes of interactions, these compounds, by facilitating or reducing GABA-transmission, are able to induce a wide spectrum of pharmacological responses (Polc et al., 1982). In many biochemical and neuro-pharmacological aspects, the behavior of a system in vivo differs dramatically from that studied in vitro. It is not usually possible to systematically relate the actions of drugs at the molecular and neuronal level to their direct behavioral effects in the intact subject. This calls for the use of a noninvasive technique. The only methodology existing today for investigating brain receptor function atraumatically is Positron Emission Tomography (PET), a safe, noninvasive visualization technique. PET accurately and quantitatively represents the spatial distribution of a positron-emitting radionuclide in any desired transverse section of the body. The PET approach may be compared to quantitative autoradiography with the advantage of allowing in vivo studies in humans under physiological and pathological conditions. In order to improve our understanding of the mechanism underlying the in vivo convulsant actions of drugs that induce generalized seizures, an attempt was made to relate simultaneously the convulsant effects of drugs acting at different binding sites of the supramolecular complex with their interactions with the benzodiazepine receptor.

Keywords

Positron Emission Tomography Inverse Agonist Generalize Epilepsy Subconvulsant Dose Convulsant Dose 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Birkhäuser Boston, Inc. 1990

Authors and Affiliations

  • M. Mazière
  • E. Brouillet
  • M. Kunimoto
  • M. Khalili-Varasteh
  • Ph. Hantraye
  • R. H. Dodd
  • D. Fournier
  • B. Guibert
  • C. Chavoix

There are no affiliations available

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