This is a request for renewal of a Research Scientist Award to allow the applicant to continue studying the role(s) of excitatory transmitters in neuropsychiatric disorders. The applicant has shown that the excitatory amino acids (EAA), glutamate (Glu) and aspartate, which are major excitatory transmitters in the CNS, have potent neurotoxic (excitotoxic) activity which is mediated by EAA synaptic receptors. Several EAA receptor subtypes have been identified and, very recently, new classes of EAA antagonists were discovered (e.g., agents in the phencyclidine/sigma opiate family) which penetrate blood brain barriers. Recent evidence suggests that endogenous EAA may be responsible for neuronal degeneration in conditions such as anoxia/ischemia, hypoglycemia and epilepsy. A major aim of the proposed research is to clarify the mechanism(s) of, and develop appraoches for preventing, EAA-mediated neuronal dgeneration in both the adult and developing CNS. In addition to exploring the role of EAA in hypoxic/ischemic and epilepsy-related brain damage, the applicant will study the relationship between EAA and phencyclidine (PCP) receptors and explore the potential role of EAA receptors in schizophrenia or other psychotic processes and in the physiology and pathology of memory and learning. His studies will also focus on the other major excitatory transmitter system in mammallian brain--the cholinergic system. He will continue to study the role of excitatory transmitters (both glutamergic and cholinergic) in cognition and the cognitive deficits in Alzheimers Disease and will continue to explore mechanisms by which lithium enhances the epileptogenicity and the neurotoxic potential of cholinergic agonists such as pilocarpine. A number of animal models, both in vitro and in vivo, will be employed, as will various methods spanning several disciplines, including light and electronmicroscopic neuropathology, immunohistochemistry, receptor autoradiography, electrophysiology, neuropsychology, neurotoxicology, neuropharmacology and neurochemistry.
