We have recently discovered that elevation of GABA or the stimulation of GABA receptors restricted to the midbrain, but not in the forebrain or hindbrain, confers protection against electroshock and chemoconvulsant-induced tonic-clonic seizures in rats. Moreover, we have localized this effect to the immediate vicinity of the substantia nigra. to our knowledge, this is the first demonstration of an anatomically selective action of GABAergic drugs with respect to anticonvulsant activity. We would now like to extend these observations by further characterizing the GABA-related mechanisms at this site responsibile for the attenuation of generalized seizures. Our characterization will include a determination of the pharmacological specificity of the effect as well as an analysis of electrographic correlates of the anticonvulsant activity elicited from substantia nigra. Furthermore, we intend to extend our analysis to other neuromodulatory systems in substantia nigra, such as the inputs containing the neuroactive peptides substance P and dynorphin. Characterization of the site at which drugs can act to control seizure propagation is important both for the understanding of mechanisms involved in seizure disorders as well as the design of novel anticonvulsant therapies. Recent work in the neuropharmacology of epilepsy has tended to concentrate on the actions of drugs at the seizure focus, in seizure initiation, or in isolated neuronal systems. A special feature of our approach is the emphasis on neural networks in the brain for the control of seizure susceptibility; we propose to investigate specific neural circuitry in the brain which may potentially exert widespread influence on central nervous system excitability. Despite its apparently pivotal role in seizure propagation, the neural system we are studying (i.e. the basal ganglia) has received relatively little attention in the context of current epilepsy research; the results of the studies outlined in this proposal therefore may help to place the genesis and control of epileptic disorders in a new perspective. In turn, this information may better define the relationship between basal ganglia circuits and regulation of central nervous system excitability.
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