The research plan will focus upon the study of the phencyclidine (PCP)-induced psychotic state as a model system for schizophrenia. The ultimate scientific goal is to discover molecular and cellular-level mechanisms related to the PCP receptor-endogenous ligand system which may be involved in the pathogenesis of endogenous psychotic illnesses, and the study of which may lead to the development of specific interventions at that system to ameliorate schizophrenic symptomatology. During phase I, experiments will be conducted to answer critical, previously unresolved questions concerning the molecular and cellular mechanisms responsible for PCP psychotominetic actions. Specific, targeted lesioning techniques will determine the neurochemical class of terminals upon which PCP receptors are localized, as well as their relationship to the synapse. The rapid filtration PCP radioreceptor assay and autoradiographic techniques will be utilized to determine PCP receptor densities and distributions after brain lesioning. In view of data suggesting a functional angatonism in brain between PCP receptors and the NMDA class of glutamate receptors, the precise molecular mechanism of the PCP-NMDA interaction will be determined. Activities of series of ligands of each of these receptor types will be determined at the other to test for a direct receptor-level interaction. Biochemical approaches including N-ethyl maleimide inactivation paradigms will determine the nature of any mutual allosteric regulation. Solubilization techniques modeled after those which have succeeded for other receptor classes will be modified to determine specific biochemical and structural characteristics of the PCP receptor moiety. In phase II, clinical applications of the basic techniques will have been developed in animal models for applicaiton to clinical subjects after specific approval has been obtained. The PCP radioreceptor assay will be employed to determine CSF levels of endogenous material with PCP-like receptor activity, which when applied to the clinical situation may yield direct evidence for a role of the PCP receptor system in endogenous psychosis. PCP receptors will be assayed on peripheral blood elements in an effort to develop a clinically useful peripheral marker of central PCP receptor activity. The formal educational program, modeled upon the Ph.D. program in neuroscience, will provide the applicant with the scientific knowledge base and specific laboratory techniques which will enable him to conduct the proposed research.
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