In this application for a Physician Scientist Award, I propose a training program which will provide me with neuroanatomical techniques to study the role of acidic amino acid (AAA) and cholinergic transmitters in epilepsy and epilepsy-related brain damage. The studies will include investigation of lithium- cholinergic limbic seizures with emphasis on elucidation of the mechanisms involved in the temporal and spatial development of seizure-related brain damage. Although the seizures observed in this syndrome are presumably initiated by excessive activation of the cholinergic system, I am interested in exploring the hypothesis that the brain damage associated with this seizure syndrome is primarily a product of excessive activity in AAA pathways. Specifically, I propose to use neuronanatomical and receptor binding techniques to assess the relative contributions made by cholinergic and AAA mechanisms in the pathogenesis of the seizure and seizure-related brain damage. Additional studies are planned to test the hypothesis that AAA antagonists will block seizures and seizures-related brain damage in the lithium- cholinergic model, and in two models of sustained focal seizures which have been shown to exhibit excitotoxic lesions. The sustained focal seizure models will also allow a test of the hypothesis that intracerebral injections of known AAA antagonists are capable of blocking seizure-related brain damage independent of a generalized anticonvulsant effect. Such a finding would add support to the belief that AAA play a crucial role as toxins in seizure-related neurodegeneration. Further studies are proposed using a simple in vitro chick retinal preparation to test agents that cross blood-brain barriers for their ability to antagonize the neurotoxicity of AAA. These agents can then be administered systemically and studied for anticonvulsant and antiexcitotoxic properties in the in vivo seizure-brain damage models. Finally, the lithium-cholinergic seizure model provides in opportunity to study the mechanisms by which lithium, an agent widely used in psychiatric chemotherapy, potentiates the excitatory activity of cholinergic agents in the central nervous system. Accordingly, the proposed research includes experiments aimed at clarifying the mechanisms underlying the interaction of lithium with the cholinergic system.
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