NEUROTRANSMITTER MECHANISMS IN EPILEPSY

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The proposed project will examine neurotransmitter mechanisms involved in seizures in genetically epilepsy-prone rats (GEPRs). The GEPR is abnormally susceptible to thermal, electroshock, convulsant, hyperbaric, kindling and audiogenic seizures (AGS) and has been shown to be a valid model of certain forms of human epilepsy. The brainstem auditory nuclei, particularly the inferior colliculus (IC), as well as the substantia nigra and brainstem reticular formation play important roles in initiation and propaga- tion of seizures in this naturally-occurring model of epilepsy. Extensive evidence indicates that neurotransmitter abnormalities. Recent iontophoretic, microinjection, histochemical, and neurochemical evidence indicates that the actions of GABA and excitant amino acids are altered in the IC of the GEPR. This proposal will examine the neuronal mechanisms subserving epileptogenesis in freely moving GEPRs and examine the effects of anticonvulsants on these mechanisms. These anticonvulsants include excitant amino acid antagonists and will be administered systemically and by focal microinjection into specific brain regions. We have successfully produced susceptibility to AGS in normal rats by focal injection of an excitant amino acid into the IC, but the convulsions lack the tonic components seen in the GEPR. Norepinephrine and 5-hydroxytryptamine deficits are reported in the GEPR, and we will attempt to reproduce the maximal seizures of the GEPR by microinjection of an excitant amino acid into the IC of normal rats while simultaneously blocking noradrenergic or serotonergic function in other nuclei of the seizure pathway. This approach has resulted in AGS with tonic components in preliminary studies. The seizure severity increases in the GEPR with the appearance of epileptiform EEG changes following daily repetition of AGS. This proposal will investigate the neural mechanisms subserving this severity increase and examine the effects of anticonvulsants on its development. The GEPR is generally more susceptible to other seizure-inducing stimuli, but is not clear if the brain sites and mechanisms involved in this general susceptibility are the same as those involved in AGS. Therefore, the proposal will utilize focal microinjection into specific brain regions of substances affecting excitant and inhibitory amino acid action to assess effects on hyperbaric seizures in the GEPR. These studies should yield significant new information about neurotransmitter mechanisms in a naturally-occurring, life-long genetic model of generalized epilepsy which could be of great value in increasing our understanding of mechanisms of epileptogenesis and increase our understanding of how certain new potentially useful anticonvulsant drugs act to prevent seizures.