NEUROTRANSMITTER SEIZURE MECHANISMS

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This proposal will utilize neuropharmacological techniques in order to evaluate neurotransmitter mechanisms involved in seizures in the genetically epilepsy prone (GEP) rat. The GEP rat is highly susceptible to thermal, electroshock, convulsant and sound-induced seizures and may serve as a useful genetic model of certain forms of human epilepsy. Previous studies indicate that the inferior colliculus (IC) and brain-stem reticular formation play critical roles in the production of seizures in this naturally-occurring model of epilepsy. Neurochemical evidence and pharmacological studies indicate that neurotransmitter abnormalities occur in the brains of these epileptic animals. Our preliminary studies and recent data from other laboratories suggest that a reduced effectiveness of the action of GABA may occur in this epilepsy model. This may result in the increased incidence of onset-offset responses to auditory stimuli in the GEP rat that we have observed in preliminary studies. The normal interaction of norepinephrine with GABA may also be altered in this epileptic animal. The proposed study will investigate if the action of these putative neurotransmitters is abnormal in IC neurons in the GEP rat. The effects on seizure susceptibility of local (cannula) implantation into IC, reticular formation and superior colliculus of agents which affect these neurotransmitters will also be examined in order to determine the importance of these structures in the seizure pathway. The excitatory amino acids, glutamate and aspartate, are implicated as possible excitatory neurotransmitters in the IC. Our preliminary studies suggest that an antagonist of these agents will significantly reduce seizure severity in the GEP rat. Therefore, we will examine the effects on IC neuronal responses of these excitatory agents and their antagonists. Since abnormalities have been reported in the cochlea of GEP rats, the response patterns of auditory neurons in the cochlear nucleus and superior olivary complex will be investigated to determine if response abnormalities occur in these nuclei which project to IC. 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 increasng our understanding of mechanisms of epileptogenesis.