Hypofunction of inhibitory GABAergic systems is thought to be a primary aspect of seizure disorders. Past researchers have attempted anticonvulsant therapy by the systemic administration of GABAmimetics. The rationale for these experiments was that the administered GABA agonists would augment the action of endogenous GABA and reduce the excitability of epileptic foci. Some of these experiments have had the paradoxical result that administration of these agonists has exacerbated seizure activity and has also produced epileptiform activity in previously seizure-free control animals. Data from Preliminary Experiments are consistent with the suggestion that this seizure activity occurs because the exogenous GABA agonists desensitize GABA receptors in the brain and render those receptors unresponsive to endogenous GABA. This would further disinhibit epileptic foci and would exacerbate seizure activity. The in vitro rat hippocampal brain slice preparation will be used to study the role that GABA receptor desensitization may have in the genesis of these epileptiform side effects of GABA-mimetic therapy. This is an appropriate preparation to be used for the investigation of this question as its epileptogenic properties have been well described. It is preferable for detailed electrophysiological analysis than the in vivo preparation because both intracellular and extracellular recordings made from individual neurons are stable for several hours. The application of drugs can also be done in a controlled manner. GABA agonists will be applied in the fluid bathing the tissue to mimic the systemically applied drug. Specific GABA receptors will be activated using the technique of ionophoresis. The technique of voltage clamping will also be used. The specific questions to be asked are 1) What are the characteristics of the epileptiform activity produced by bath applied GABA agonists? Preliminary experiments indicate that bath application of muscimol causes afterdischarged often followed by spreading depression. This activity is accompanies by the loss of intracellularly recorded IPSPs. 2) What are the desensitization properties of their three types of GABA receptors in the brain slice when activated by GABA agonists? 3) Is desensitization of any of these receptors responsible for the muscimol produced epileptiform activity? 4) Are there any GABA agonists whose action on the different GABA receptors is such that the net effect is inhibition? The discovery of such agonists would subserve the long-term goal of finding good candidates for effective GABAmimetic anticonvulsant therapy.
|Chesnut, T J; Swann, J W (1990) Suppression of 4-aminopyridine-induced epileptogenesis by the GABAA agonist muscimol. Epilepsy Res 5:8-17|
|Chesnut, T J; Swann, J W (1989) Disinhibitory actions of the GABAA agonist muscimol in immature hippocampus. Brain Res 502:365-74|