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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Physician Scientist Award (K11)
Project #
5K11MH000631-03
Application #
3087936
Study Section
Research Scientist Development Review Committee (MHK)
Project Start
1986-07-01
Project End
1991-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
Zylberman, I; Javitt, D C; Zukin, S R (1995) Pharmacological augmentation of NMDA receptor function for treatment of schizophrenia. Ann N Y Acad Sci 757:487-91
Javitt, D C; Frusciante, M J; Zukin, S R (1994) Activation-related and activation-independent effects of polyamines on phencyclidine receptor binding within the N-methyl-D-aspartate receptor complex. J Pharmacol Exp Ther 270:604-13
Javitt, D C; Zylberman, I; Zukin, S R et al. (1994) Amelioration of negative symptoms in schizophrenia by glycine. Am J Psychiatry 151:1234-6
Javitt, D C; Schroeder, C E; Steinschneider, M et al. (1992) Demonstration of mismatch negativity in the monkey. Electroencephalogr Clin Neurophysiol 83:87-90
Nussenzveig, I Z; Sircar, R; Wong, M L et al. (1991) Polyamine effects upon N-methyl-D-aspartate receptor functioning: differential alteration by glutamate and glycine site antagonists. Brain Res 561:285-91
Javitt, D C; Zukin, S R (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301-8
Javitt, D C; Zukin, S R (1990) The role of excitatory amino acids in neuropsychiatric illness. J Neuropsychiatry Clin Neurosci 2:44-52
Javitt, D C; Frusciante, M J; Zukin, S R (1990) Rat brain N-methyl-D-aspartate receptors require multiple molecules of agonist for activation. Mol Pharmacol 37:603-7
Javitt, D C; Zukin, S R (1989) Biexponential kinetics of [3H]MK-801 binding: evidence for access to closed and open N-methyl-D-aspartate receptor channels. Mol Pharmacol 35:387-93
Sircar, R; Frusciante, M J; Javitt, D C et al. (1989) Glycine reverses 7-chlorokynurenic acid-induced inhibition of [3H]MK-801 binding. Brain Res 504:325-7

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