ON THE PHARAMACOLOGY OF CONVULSANT DRUGS

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The project is a continuing effort to explore neuronal mechanisms subserving the ability of sensory stimuli to initiate seizure in animal models including treatment with subthreshold doses of convulsant drugs. These models enable exploration of neuronal responses to a controllable stimulus which is capable of initiating a seizure and reveals information about the role of neurons in different brain regions in seizure initiation. The prominent organizational aspects of generalized seizures, demonstrated by the simultaneous onset and offset of seizure activity throughout the brain which are difficult to study in vitro can be examined. Our findings indicate that over 90% of brainstem reticular formation (RF) neurons undergo striking changes in sensory responsiveness from being unresponsive to being quite responsive after treatment with subconvulsant doses of 10 different convulsant drugs, while neurons in lateral geniculate, hippocampus and amygdala show only minor changes. Neurons in pericruciate cortex show smaller changes than those in RF, but a striking convulsant-induced cross-correlation of firing between reticular formation and pericruciate cortical neurons is observed. The abnormally extensive convulsant-induced entrainment of RF neuronal firing could precipitate seizure generalization through an afterdischarge-like effect. Because of widespread connections of the RF to other brain regions, this excessive neuronal discharge may spread throughout the brain, triggering a generalized seizure. Such a process may be reflected in the striking convulsant-induced correlation of firing of MRF and pericruciate neurons. We will also examine the changes in firing of diencephalic sites which project from RF to pericruciate. This study will examine the generality of enhanced sensory responsiveness in additional models of seizure including the Genetically Epilepsy Prone (GEP) rat and the neocortical penicillin focus. The possible synaptic mechanisms subserving the abnormal response observed in neurons of the GEP rat will be examined by observing if putative excitatory neurotransmitters and antagonists of inhibitory neurotransmitters can produce the afterdischarge response in normal neurons seen prominently in GEP neurons. The neuronal responses in substantia nigra will be evaluated in GEP rat and with convulsant drugs to determine the contribution of this important structure to seizure mechanisms in these models. Completion of these experiments should yield significant new information applicable to understanding seizure initiation by sensory stimuli which is observed in human epilepsy.